Pondering Pentoxifylline for Peripheral Arterial Disease

Pondering Pentoxifylline for Peripheral Arterial Disease

Marlo Garner BSc (Pharm) Interior Health Pharmacy Resident

September 8th 2011

Learning Objectives

• At the end of this session you should be able to:

– Describe the pathophysiology of peripheral arterial disease

– Describe the theory of how pentoxifylline works

– Be able to describe the evidence for peripheral arterial disease

Outline

• Meet the Patient

• Peripheral Arterial Disease

• Clinical Question

• Review Evidence for Pentoxifylline

• Therapeutic Plan

Meet the Patient J.G.

ID: 75 yo female admitted August 20th, 2011 to the medical teaching unit

CC / HPI: Pain in left great toe Sharp pain radiating up leg 9/10, unable to manage at home Ongoing x 3 weeks Minimal relief with analgesics

Allergies: Celecoxib – hives Acetaminophen – “doesn’t fell good”

SHx: Lives at home with spouse No Etoh Quit smoking 25 years ago

Meet the Patient J.G. PMHx: MPTA:

Pulmonary Arterial Hypertension

Bosentan 125mg po BID Ipratropium 2 (40mcg) puffs QID Sildenafil 25mg po TID Salbutamol 2 (200mcg) puffs QID Warfarin 8-10mg po daily Oxygen 2-3L at home

Edema 2 PAH Furosemide 120mg po daily Metolazone 5mg po daily

Scleroderma Prednisone 7.5mg po daily

CKD

Sickle Cell Trait

Back pain (spinal stenosis)

Hydromorphone SR 3mg po AM & 6mg po HS Hydromorphone IR 2-4mg po q 6hr PRN Gabapentin 900mg po HS

GERD Esomeprazole 40mg po daily

Hypertension

Glaucoma Latanoprost 0.005% 1 drop each eye

Review of Systems Vitals T 36.6 HR 81 BP 104/57 RR 16 O2 sat 97% 2.5L

CNS A+O x 3

HEENT

CVS JVP unable to visualize, no murmurs

RESP No cough, wheeze on expiratory

GI No appetite, BS x 4

GU Cr 142 (baseline), eGFR ~31ml/min

MSK Left toe pain, swollen, red

DERM Discoloured thick skin, hypertrophic nails, chronic right foot ulcer, global edema

ENDO BG 5.9

HEME Hgb 107, MCV 80, INR 2, Plts 348, WBC 9.5,Neut 6.2

LYTES Na+ 136, K+ 3.5, Cl 89, Bicarb 30

Investigations

• X-ray Feet (Aug 20) – unlikely gout, extensive arterial calcification

• Nuclear Scan (Aug 22) – no bone activity

• Echo (Aug 23) – severe PH, moderate TR, mild AS, EF 60-70%

– LV normal, RV mildly dilated and hypertrophic

• CT Angio (Aug 29) – extensive arthromatous disease

– occluded SFA & tibioperoneal trunk

– findings suggestive of PVD caused by atherosclerosis

Course in Hospital

• PAD diagnosis

• Pt experiencing pain, although reluctant to change analgesic regimen – Hydromorphone 9mg SR po BID

– Using 12-24mg po PRN/day

• Radiology recommends Fem-Pop bypass

• Unclear if surgical candidate given co-morbidities

Current Problems & Medications Medical Problems Medications

Pain at rest 2 PAD

Hydromorphone SR 9mg po BID Hydromorphone IR 2-4mg po q2hr PRN Gabapentin 900mg po HS

Peripheral Arterial Disease

PAH Warfarin 8mg po daily Salbutamol 2 puffs (200mcg) QID Sildenafil 25mg po TID Ipratropium 2 puffs (40mcg) QID Bosentan 125mg po BID Oxygen 2-3 L

Edema 2 PAH Metolazone 5mg po daily Furosemide 120mg po daily

Scleroderma Prednisone 7.5mg po daily

Chronic Kidney Disease

GERD Pantoprazole 40mg po BID

Glaucoma Latanoprost 0.005% 1 drop each eye HS

Anemia Ferrous Gluconate 300mg po daily

Sickle Cell Trait

Hypertension

List of DRP’s • JG is experiencing pain secondary to peripheral arterial

disease and would benefit from a reassessment of her pain management.

• JG is at increased risk of a GI bleed 2 receiving warfarin for pulmonary arterial hypertension, given her history of scleroderma and would benefit from reassessment of her need for anticoagulation.

• JG is at risk of complications of peripheral arterial disease secondary to not receiving ASA and would benefit from a reassessment of antiplatelet therapy.

• JG is at risk of complications of peripheral arterial disease secondary to not receiving lipid reduction therapy and would benefit from a reassessment of lipid therapy.

List of DRP’s cont’d

• JG is at risk of experiencing adverse drug reactions secondary to receiving too high of a dose of pantoprazole and would benefit from a reassessment of her gastric protective therapy.

• JG is experiencing symptoms of anemia secondary to too low of dose iron therapy and would benefit from reassessment of anemia therapy.

DRP Focus

• JG is experiencing pain secondary to peripheral arterial disease and would benefit from a reassessment of her pain management.


http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001223/

• PVD is arteriosclerosis, or plaque build up on artery walls causing arteries to narrow

• Artery walls become stiff & cannot dilate to allow greater blood flow when needed


Symptoms Signs

•Pain •Numbness •Burning •Cramps at night •Weight of bed sheets, clothes etc •Ulcers that do not heal •Intermittent claudication -pain in legs -increased with walking or exercise -relieved at rest •Pain at rest -worse with elevation -improves when legs dangle over bed

•Painful ulcers on feet/toes (usually black) •Pale skin/blue color of toes or foot •Cool to touch •Shiny, tight skin •Hair loss over the toes and feet •Thickened toenails



• Risk Factors – Smoking

– Hyperlipidemia

– Diabetes mellitus

– Hyperviscosity



• Complications:

– CAD

– Stroke

– Critical Limb Ischemia

– Amputation


Goals of Therapy

• Reduce or alleviate symptoms

• Reduce morbidity (CVD, stroke, amputation)

• Reduce mortality

• Prevent medication related ADRs

Therapeutic Alternative for Symptom Management

• Non Pharmacological – Physical exercise

– Surgery • Fem-pop bypass

• Stent

• Amputation

• Pharmacological – ↑Hydromorphone

– Pentoxifylline

– Cilostazol

Pentoxifylline MOA Theory:

• viscosity of blood

• Improves blood flow through arteries

• ↑ blood & oxygen to muscles

http://www.virtualmedicalcentre.com/anatomy.asp?sid=30&title=Blood-Function-and-Composition

Pentoxifylline

Dose: – 400mg po TID CC

– Dosing in renal dysfunction has not been studied • ~< 60 ml/min 400mg po BID

• ~< 20 ml/min 400mg po daily (further reduction may be required

– Maximal therapeutic benefit may take 2-4 weeks

SE: – Nausea, vomiting, dizziness, heartburn

– Many other < 1%)

Lexi-comp Pentoxifylline monograph

Clinical Question

P In a 75 yo female with PVD with multiple co-morbidities and limited mobility

I Pentoxifylline

C Placebo

O Reduce/alleviate pain at rest Increase exercise Symptom free walking distance No increase in adverse affects

Literature Search Databases Medline, EMBASE, Cochrane, Google scholar, Google

Search Terms

Pentoxifylline, peripheral vascular disease, claudication, pain, human, English language

Results 32 RCT’s - mostly from 80’s and 90’s

2 meta-analysis - 1999 Girolami et al - 1996 Hood et al 1 review article - 2002 Regensteiner and Hiatt

Hood et al 1996 Design Meta-analysis of RCT’s

29 trials for pentoxifylline) 11 Included

Inclusion/ Exclusion

Inclusion - PVD - RCT 1976-1994 - Placebo controlled - Double Blinded

Intervention/ Comparator

Pentoxifylline vs placebo

Primary Outcome

Efficacy • pain-free walking distance • absolute claudication distance

CMAJ. 1996 Oct 15:155(8):1053-9

Hood et al 1996

CMAJ. 1996 Oct 15:155(8):1053-9

Results

CMAJ. 1996 Oct 15:155(8):1053-9

Limitations

• Methodologic

– No language restriction, unable to obtain German trials

– Significant heterogeneity

– Difficulty pulling data

• Clinical

– Increase in 30m of pain free walking may not be clinically significant

– Large # dropouts (unclear reason)

– ADRs not mentioned

– Pain at rest or Quality of life not assessed

Girolami et al 1999 Design Meta-analysis of RCT’s

28 eligible trials (13 trials for pentoxifylline) 15 excluded

Inclusion/ Exclusion

Inclusion - PVD - RCT’s - Placebo controlled - Blinded

Intervention/ Comparator

Pentoxifylline vs placebo Nafronyl vs placebo Physical Training vs placebo Smoking Cessation

Primary Outcome

Efficacy • Improvement in pain-free walking • Improvement in total walking

Arch Intern Med 1999 Vol 159, FEb 22, 1999

Girolami et al 1999

Arch Intern Med 1999 Vol 159, FEb 22, 1999

Results

Girolami, B. et al. Arch Intern Med 1999;159:337-345.

21 meters

[95% CI, 0.7 to 41.4m]

Limitations

• Methodologic – Quality of selection process

– Limited search to English language

– Homogeneity not clearly stated

• Clinical Application – Quality of life experienced

– Pain at rest not studied

– ADR’s not mentioned

Summary of Literature

P In a 75 yo female with PVD with mulitple co-morbidities and limited mobility

I Pentoxifylline

C Placebo

O Reduce/alleviate pain at rest Increase exercise Symptom free walking distance No increase in adverse affects

no evidence no evidence no conclusive evidence no evidence

Application to JG

• Necessary

– Unable to exercise

– May not be a surgical candidate

– Reluctant to trial higher doses of opioids

• Safe

– SE: Nausea, vomiting, dizziness, heartburn

– Dosing in renal dysfunction has not been studied

Application to JG

• Efficacy

– No evidence for efficacy (pain free walk)

– Pain at rest not studied

– May take 2-4 weeks for maximal therapeutic

• Patient specific factors

– Polypharmacy burden

Therapeutic Plan

• Pentoxifylline not an appropriate option

– Likely no benefit but increase risk of SE

• Maximize Hydromorphone

– Increase HM SR 12mg po BID

– HM IR 4mg po q2hr PRN

– Reassess pain control and PRN use

• Await vascular assessment

Monitoring Plan - Efficacy

What Who When Efficacy

S: Symptoms - pain

Pt Daily Improvement

O: Vitals: T, HR, BP, RR, O2 sats

RN Daily Remain stable

P/E: Left Toe - redness - pain on exam - ulceration

MD, RN, Rx

Q few days Improvement

Labs: Na, K, Creat

MD, Rx Daily Remain stable/baseline

HM IR usage Rx Daily Reduction in PRN medication use

Monitoring Plan Safety What Who When Safety

S: Symptoms - drowsiness - constipation

Pt Daily Symptoms of medication related ADR’s

O: Vitals: T, HR, BP, RR, O2 sats

RN, Rx Daily Signs of medication related ADR’s

P/E: - vomiting - bowel movements

MD, RN, Rx

Daily

Labs: Na, K, Creat

MD, Rx

Follow Up

• Pt reluctant to increase hydromorphone

• Vascular assessed patient

• Amputation of left toe & stent

Questions

Guidelines

Pondering Pentoxifylline for Peripheral Arterial Disease

Documents

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