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Rosanne Thalakada, BSc, BSc (Pharm), ACPRPharmD Candidate 1T3
PHM 706 SeminarJuly 4, 2012
Are Cannabinoids Effective For The
Treatment of Neuropathic Pain?
Outline
Case Drug Therapy Problems (DTPs) Overview of neuropathic pain Neuropathic treatment Clinical question Review of the literature Recommendation Monitoring
Learning Objectives
Describe neuropathic pain and goals of therapy
Describe the pharmacological and non-pharmacological treatments for neuropathic pain
Evaluate the efficacy and place of therapy for cannabinoids for treatment of neuropathic pain
Meet Mr. KY
51 year old male NKDA CC: Drowsiness and uncontrolled
chronic back pain (7/10) HPI: 2 weeks
Referred to the pharmacist: June 27, 2012 (for medication review)
Past Medical History
Neuropathic pain (hip, ankles, back) Depression (stable) Post-traumatic Stress Disorder Post-polio syndrome falls Hepatitis C Obstructive Sleep Apnea GERD
Social History
Lives alone Past smoker 2 ppd x 40y Past marijuana user Past heavy alcohol use x 20 years Past user of crystal meth, heroine,
cocaine Past opiate addiction
2
Medication history
Morphine ER 15mg PO once daily x 3 months
Nabilone 0.5mg PO BID (recent start) Senna 1 tab PO BID Lactulose 30ml PO BID Pantoprazole 40mg PO BID Escitalopram 20mg PO daily Nicotine patch 21mg top daily
Review of systemsVitals T 36°C, BP 120/86mmHg, HR 88 regular, RR 18
CNS Neuropathic pain 7/10 (Hip, ankles, back)Drowsiness
HEENT Normal
Resp Normal WOB, clear, no SOB
CVS Normal perfusion, no murmur, no chest pain
GI/GU Constipation (BMs q2-3d; his normal = 1qd)
Kidney/Liver SCr 43 umol/LAST/ALT 2x UNL, albumin WNL, PTT/INR WNL
Endocrine HbA1c 5.8%
Heme/lytes/ fluid
WNL
MSK/skin Unremarkable
Drug Therapy Problems
1. KY is experiencing adverse drug reactions to morphine (drowsiness and constipation)
2. KY is receiving ineffective therapy (morphine) for his neuropathic pain (burning, shooting pain in hips, ankle, back)
3. KY is experiencing uncontrolled neuropathic pain secondary to not receiving a breakthrough pain medication
4. KY is at risk for a relapse of opiate addiction secondary to receiving morphine
5. KY is at risk of worsening of his OSA secondary to receiving sedating medications (morphine, nabilone)
6. KY is at risk for adverse drug reactions secondary to receiving a high dose of pantoprazole for GERD (headache, diarrhea, CDAD)
Drug Therapy Problems cont’d
Chronic pain1
1 in 5 people Prevalence increases with age More people are surviving cancer, HIV
and CV disease however are afflicted with chronic pain
Chronic pain has a significant affect on QOL
Neuropathic pain vs Nociceptive pain2
Nociceptive– Sprains, bone fractures, burns, bruises,
inflammation – Usually time limited and responds to treatment
Neuropathic– Damage to the peripheral/central nervous
system– Burning, shooting, shock-like, tingling– Usually chronic and difficult to treat
3
Neuropathic pain
Nerve damage
Inflammation, ectopic excitability, ↑sensory transmission, nerve structure
changes, ↓ pain inhibition1
Goals of therapy
Goal Time frameReduce pain by 30% - 50% ideally to tolerable level
2 weeks
Reduce symptoms of drowsiness and constipation
1 week
Improve/maintain QOL (maintain ADLs)
2 weeks and ongoing
Prevent complications of chronic pain (depression, anxiety, ↓sleep)
1 week and ongoing
Neuropathic pain – Treatment (CPS guidelines)3
1st Line TCAs Anti-convulsants (gabapentin, pregabalin)
2nd Line SNRIs (venlafaxine, duloxetine) Topical lidocaine
3rd Line Tramadol Opioids CR
4th Line Cannabinoids Methadone Anti-convulsants (lamotrigine, topiramate, valproic acid)
Marijuana & Cannabinoids1
Has been used for centuries as an herbal remedy and intoxicant
Approved for the treatment of refractory CINV
Have been used for treatment of pain since the ’70s
Mechanism of action
Nabilone
CB1 CB2(CNS) (Immune system)
G- protein activation
↓neurotransmitter release (serotonin, dopamine, glutamate)
Clinical question
P In a 51 year old male with chronic neuropathic pain
I Nabilone 0.5mg PO BID
C Compared to placebo
O Reduce neuropathic pain?
4
Search strategy
Pubmed/Medline, Embase
Search terms:– Cannabinoids, nabilone, neuropathic pain,
chronic non-cancer pain: 2 systematic reviews, 28 studies, 100+
review articles
Are cannabinoids an effective and safe treatment option in the
management of pain? A qualitative systematic review
Campbell, FA. et al4 2001
Campbell et al 20014
Design Systematic review
P -9 RCTs with 202 adult patients-128 pts cancer pain-72 post-operative pain-2 chronic non-malignant pain
I -Oral THC 5-10mg-THC (NIB) 4mg-Benzopyranoperidine (BPP)-levonantradol 1.5-3mg IM
C -Codeine 60-120mg-Secobarbital 50mg-Placebo
O -Primary outcomes – Pain relief-Secondary outcomes – Adverse Drug Reactions
Outcomes Cancer PainBPP = PlaceboTHC 10mg = Codeine 60mgTHC 20mg = Codeine 120mg (↑↑ SEs)
THC (NIB) = Codeine 50mg = Secobarbital 50mg(↑↑ SEs)
Chronic non-cancer painTHC 5-10mg = Placebo (Pain intensity)THC 5-10mg > Placebo (↓ morphine breakthrough)Neuropathic pain + spasticity:THC 5mg = Codeine 50mg > Placebo
Post-operative painLevonantradol IM > Placebo
Campbell et al 20014
Outcomes Adverse Effects Dose response Mental clouding, ataxia, dizziness, numbness, disorientation, disconnected thought, slurred speech, impaired memory, dry mouth, blurred visionTHC 5-10mg PO generally well tolerated
Limitations• Small studies• Cross-over design• Short duration• Older studies – did not examine Nabilone, Sativex• Did not examine as adjunct therapy
Campbell et al 20014
Cannabinoids for treatment of chronic non-cancer pain;
a systematic review of randomized trials1
Lynch, M. & Campbell F. 2011
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Design Systematic reviewP -18 RCTs
-Neuropathic, HIV neuropathy, fibromyalgia, MS, rheumatoid arthritis
I -Cannabinoid (smoked cannabis, nabilone, dronabinol, cannabis-based medicine (CBM))
C -PlaceboO -Primary outcomes – Pain intensity
-Secondary outcomes – Quality of Life, AEs
Lynch, M. & Campbell F. 20111Primary Outcome(Pain intensity)
-Smoked cannabis > Placebo (neuropathic pain, HIV neuropathy)
-CBM > Placebo (neuropathic pain)
-Nabilone 0.5 -1mg PO BID > Placebo (spinal pain, fibromyalgia, spasticity-related pain)
-Nabilone 2mg OD > dihydrocodeine 240mg OD(neuropathic pain)
-Dronabinol 10-20mg OD > Placebo (MS)
-CBM > Placebo (Pain intensity at 3h)
Lynch and Campbell 20111
Secondary Outcomes(QOL and AEs)
QOL-Largely no difference-1 trial Nabilone > Placebo (fibromyalgia)
AEs-No serious AEs-Most common = sedation, dizziness, dry mouth, nausea, inability to concentrate, poor coordination, ataxia, headache, paranoia, agitation, euphoria, dysphoria
Lynch and Campbell 20111
Limitations• Small studies• Short duration• Potential for abuse not studied (? Long term risk)• Only some investigated nabilone as adjunct therapy• Is the pain relief clinically meaningful?
An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with
peripheral neuropathy
Besterd JA and Toth CC 20105
Besterd and Toth 20105
Design -Prospective, open label
P -Chronic neuropathic pain-n=220
I -Monotherapy (Nabilone 3mg daily or gabapentin 2,400mg daily) N=101-Adjuvant therapy (Add on either nabilone 3mg daily, gabapentin 2,300mg daily) N=119
C -Control
O -Primary outcomes (3mos, 6 mos)– Quantity and quality of pain (VAS)
-Secondary outcomes – Health status, QOL, AEs
Besterd and Toth 20105
Primary Outcomes(Pain quality & quantity)
Monotherapy (N or G)Sig. ↓ pain after 3 and 6 mos vs baseline6 mos > 3 mos
Adjuvant therapy Sig. ↓ pain after 3 and 6 mos vs baseline6 mos > 3 mos
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Besterd and Toth 20105
Secondary Outcomes(Health status, QOL, AEs)
Health status, QOLNo sig. difference health status, QOLExcept ↑ sleep, ↓ pain, ↓ discomfort
AEs-no serious AEsMost common: sedation, dizziness/lightheadedness, fatigue
Recommendation -Pharmacological
Reduce morphine by 5mg weekly Continue nabilone 0.5mg PO BID
– Titrate to 2-3mg PO daily Add tramadol 25mg PO daily
– Increase by 25mg PO q3-5d to 50-150mg PO QID
– Once at stable dose, change to long acting + breakthrough
Tramadol contract Pain diary TENS Exercise, ? acupuncture (refer to physiotherapy) Behavioural therapy (refer to psychology)
Recommendation –Non-pharmacological Rationale
Ruling out: Gabapentin (previously ineffective) Pregabalin (gabapentin ineffective) Topical products due to the large area
involved TCAs and SNRIs (↑ risk for serotonin
syndrome with escitalopram) Methadone (challenging to titrate,
prescribing restrictions) Anti-epileptics (4th line agent)
Other recommendations
Pantoprazole Reduce to 40mg PO daily
Senna and lactulose Continue as ordered
Referral to physiotherapy
Exercise, ? Acupuncture, TENS
Referral to psychology Behavioral therapy
Monitoring - Efficacy
Parameter Change Who When
CNS ↓ Neuropathic pain by 30% - 50% ideally to tolerable level↓ Drowsiness
MD/Pharm 2 weeks
GI/GU ↓ Constipation MD/Pharm 2 weeks
QOL Maintain or improve daily functioning
Pharm/Psych
2 weeks
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Monitoring - SafetyParameter How Who When
Side effects to nabilone
↓ drowsinessNo dizziness, dry mouth, addiction
MD/Pharm 1 week
Side effects tramadol
No dizziness, vertigo, asthenia
MD/Pharm 1 week
Withdrawal to morphine
N/V, sweating, headache
MD/Pharm 1 week
Serotonin syndrome
No rigidity, hyperreflexia, sweating, tachycardia
MD/Pharm 1 week
References
1. Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol. 2011 Nov;72(5):735-44
2. Baumann T, Strickland J, Herndon C. Pain Management. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 8th ed. Toronto: McGraw-Hill, Medical Publishing Division; 2011. p.1045-1059.
3. Moulin DE, Clark AJ, Gilron I. et al. Pharmacological management of chronic neuropathic pain – Consensus statement and guidelines from the Canadian Pain Society. Pain Res Manage 2007; 12(1): 13-21
4. Campbell FA, Tramèr MR, Carroll D, Reynolds DJ, Moore RA, McQuay HJ. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ. 2001 Jul 7;323(7303):13-6.
5. Bestard JA, Toth CC. An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. Pain Pract. 2011;11(4):353-68
Thank you
Questions?
04/07/2012
1
THE USE OF CLOZAPINE FOR THE MANAGEMENT OF NON-SCHIZOPHRENIC PSYCHOGENIC POLYDIPSIA – A PATIENT CASE REPORT
Zoe Wong
B.Sc. Phm-Pharm D candidate (2013)July 4, 2012
Outline
1) Patient case – K.R.
2) Overview of Psychogenic Polydipsia
3) Summary & appraisal of the literature
4) Care plan
Patient – K.R.
58 y.o. female Increased anxiety, agitation and excessive daily intake
of fluids since Nov. 2011 – diagnosed with psychogenic polydipsia
Social history: homelessness separated from her husband & estranged from her son minimal contact with her sister
cigarette smoking - 1 pack per day alcoholism - ≥6 beers per day no recreational drug use
Patient – K.R.
Family history: non-contributory
NKA
Past medical history: 19 ED visits since Dec. 1992 for a range of injuries
due to falls and physical abuse
Only prior Mental Health admission was in Dec. 2010 for depression
History of Presenting Illness
Sept. 2011 – admitted to ED at TEGH with intracranial hemorrhage due to head trauma after a fall
Nov. 2011 – found to have limited rehab potential at Acquired Brain injury Program at Toronto Rehab
Dec. 2011
ICU admission for acute hyponatremia (serum Na of ~109 mmol/L) & seizure
restraints in CCC for increasing agitation and attempts to obtain fluid
History of Presenting Illness
Jan. – Feb. 2012 – transferred to 5-bed locked unit in Psychiatric Ward
stabilized on Gatorade™ ½ c. q30min, 24-hr monitoring and behavioural intervention
Mar. – Jun. 2012
awaiting placement in CCC
minimal improvement in water-seeking behaviour
constant exit-seeking behaviour with 3 Code Yellows
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Psychiatric Assessment
minimally cooperative to interview; frequent requests to go to the bathroom
Mental Status Exam (MSE) score of 18/30 suggesting moderate cognitive impairment appears much older than stated age alert, orientated to place but not time gait with small shuffling steps irritable, restricted affect slurred speech poor judgment lack of insight
Serum Sodium (Sept. 2011 to June 2012)
ICU
Psych ward
CCC
CCC
Current Medications
Indication Medications
Psychogenic polydipsia
- Seizures
Quetiapine XR 100 mg PO qdinnerLosartan 12.5 mg PO daily
Phenytoin 400 mg PO qHS
Depression Sertraline 75 mg PO qdinner
Anxiety Clonazepam 0.5 mg PO BIDLorazepam 0.5-1 mg PO/SL q4h PRN
Sleep Trazodone 100 mg PO qHS
Psychogenic Polydipsia (PPD)
Excessive water consumption in the absence of a physiological stimulus to drink
Epidemiology: 6-20% of psychiatric patients ~80% of whom have schizophrenia also associated with middle-aged women with anxiety disorders
& patients with developmental disabilities (e.g. autism)
Etiology: unclear but likely multifactorial positive symptoms of schizophrenia compulsive behaviour method of stress reduction attempt to counteract anticholinergic effects
Psychogenic Polydipsia (PPD)
Pathophysiology: unclear; likely related to malfunction of the hypothalamic thirst centre higher set point for thirst suppression than for suppression of antidiuretic
hormone (ADH) secretion
Clinical presentation: water-seeking and drinking observed by others 10-20% characterized by hyponatremia (serum Na < 135 mEq/L) but
usually mild/asymptomatic symptoms more likely after acute consumption of 3-4 L of fluids, or in
excess of the kidney’s short-term excretion capacity (10-15 L/d)
Diagnosis: by exclusion of other causes of hyponatremia
Potential Contributing Factors in K.R.
head trauma brain injury cognitive impairment
underlying psychiatric illness depression, anxiety
chronic alcohol use; malnourishment cigarette smoking haloperidol use while hospitalized ADH increases due to stress, nausea
04/07/2012
3
Clozapine
Atypical antipsychotic antagonist at dopamine receptors (greater affinity for D4 vs. D2), 5-HT2
receptors, as well as adrenergic and histaminergic receptors
Indicated for management of symptoms of treatment-resistant schizophrenia only agent with proven efficacy in treatment resistant-schizophrenia, and
for reducing hostility and aggression, persistent suicidal behaviour and all-cause mortality
Patients on clozapine, treating physicians and dispensing pharmacies are all enrolled in registries mandatory regular monitoring of blood work & verification by Clozaril
Support and Assistance Network (CSAN)
Not officially indicated for PPD but is the agent with the most evidence and experience
Clinical Question
P
I
C
O
Patients with psychogenic polydipsia who have had at least one episode of hyponatremia (±seizure)
Clozapine (+ behavioural intervention)
Any other pharmacological and/or behavioural intervention
Objective decrease in polydipsia and number/severity of hyponatremia episodes
Clozapine in Psychogenic Polydipsia
Summary of the Literature
Evidence for Clozapine
Type Articles
Cohort Spears et al (1996)
Case-control Canuso & Goldman (1999)
Case series Verghese et al (1998) – only 2 ptsFuller et al (1996)de Leon et al (1995)
Case reports Non-schizophrenic Schizophrenic
Margetic et al (2006)de Leon et al (2003)Mauri et al (2002)
Diniz et al (2010)Wakefield & Colls (1996)Gupta & Baker (1994)Lee et al (1991)
Efficacy of clozapine in a non-schizophrenic patient with PPD and central pontine myelinolysisMauri et al (2002)
52 y.o. female with 4-yr history of PPD previously treated with clomipramine, amitriptyline, fluvoxamine
and carbamazepine (at standard doses for adequate time frames) without success
hospitalized for water intoxication after consuming >20 L of water in a day (serum Na of 101 mmol/L) diagnosed with dependent personality disorder (DSM-IV) central pontine myelinolysis detected on cerebral MRI
initiated clozapine 25 mg/d, then gradually increased to 300 mg/d progressive reduction and eventual normalisation in water
intake, and normalisation of serum electrolytes myelinosis also improved on MRI at 22 months
symptom remission maintained at 39-month follow-up
Polydipsia – A study in a long-term psychiatric unitde Leon et al (2003)
30 y.o. female with autism and PPD discharged on clozapine
Switched to olanzapine in the community, leading to readmission to a locked unit and re-initiation of clozapine
Patient was stabilized sufficiently on 300 mg/d of clozapine to stay in a day room.
Discharged to a closely supervised environment where she was denied access to cups
Clozapine was discontinued again and switched to quetiapine, which led to another readmission where she was re-stabilized on clozapine.
04/07/2012
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Successful treatment of polydipsia, water intoxication, and delusional jealousy in alcohol dependent patient with clozapineMargetic et al (2006)
43 y.o. male with 15-yr history of alcoholism ≥2 years of multiple episodes of unpredictable behaviour family noted that she “drank litres of water” but attributed it to
alcoholism
Hospitalized 2 yrs ago for delusional jealousy, during which an episode of water intoxication occurred (urine Na 116 mmol/L and specific gravity <1.005)
Treated with water restriction to 1.5-2.0 L/d & clozapine 50 mg/dstarted same day
Clozapine dose increased to 150 mg/d over the next 10 days, during which Na normalized to 135-155 mmol/L Delusions also resolved after a few weeks
Dose gradually reduced to 100 mg/d a year later and did not result in relapse of psychosis or polydipsia
Patient in Mauri et al (2002) had long-standing PPD and found benefit with clozapine where other agents failed
de Leon et al (2003) provides better evidence of causality
Margetic et al (2006) also showed improvement in psychosis
incomplete reporting
baseline factors
final lab measurements
safety parameters
lack of consistent and/or objective outcome measures
specific co-morbidities
Strengths Limitations
Clozapine treatment in polydipsia and intermittent hyponatremiaSpears et al (1996)
Prospective cohort study P: 11 patients with schizophrenia or schizoaffective disorder
history of repeated diurnal weight gains of >10% at least one documented episode of hyponatremia in the 6
months prior to therapy
I/C: 26 wks of clozapine vs. 26 wks of standard antipsychotic medication
O: target weight protocol and serial lab measures significantly higher serum Na between 6 a.m. and 4 p.m. improved frequency, severity and estimated quantity of
polydipsia improved polydipsia and hyponatremia were associated with less
monitoring and restriction of patients, with a trend toward psychiatric improvement
Clozapine restores water balance in schizophrenic patients with polydipsia-hyponatremia syndromeCanuso & Goldman (1999)
Prospective, open-label, case control study P: 8 male inpatients with treatment-resistant schizophrenia
and hyponatremia (plasma Na <125 mEq/L) in the last month
I: conventional neuroleptic C: clozapine titrated up to 300 mg/d over 2 wks then
increased to 600 then 900 mg/d respectively over 6-wk intervals
O: plasma osmolality increased SS more with clozapine vs. conventional neuroleptic by
mean of 15.2 mOsm/kg (CI: 1.9-33.6; p<0.001) normalized on 300 mg/d, with no added benefit from higher
doses (p=0.19)
Evidence against Clozapine
Type Article
Case report
Wicki et al (1998):
• 42 y.o. male with schizophrenia treated with clozapine, and hyponatremia due to PPD
• experienced generalized seizure, creatine kinase elevation and rhabdomyolysis
• authors proposed that clozapine may increase muscle cell permeability, leading to abnormal Na-Ca exchange Ca accumulation within the cell activates proteases and lipases that lead to destruction
Indication: Psychogenic polydipsia
DTP: K.R. is at risk of complications of psychogenic polydipsia due to suboptimal therapy with quetiapine & losartan.
Care Plan
04/07/2012
5
Goals of Therapy
Prevent excessive water consumption Prevent complications of PPD:
hyponatremia water intoxification seizures, coma, death
Increase cooperation with staff, fluid restriction and behavioural interventions
Increase insight into illness Increase placement potential Enhance quality of life
Therapeutic Alternatives for PPD
behavioural modification
cognitive behavioural therapy (CBT)
behavioural intervention
fluid restriction
atypical antipsychotics: clozapine risperidone olanzapine quetiapine
propranolol demeclocycline lithium ACE inhibitors / ARBs clonidine naloxone aquaretics (i.e. conivaptan)
Non-pharmacological Pharmacological
Behavioural Intervention
Advantages Disadvantages
• low cost• no drug-related
adverse effects
• delayed onset (mostly due to non-compliance)
• time and human resource intensive
• Therapeutic fluid restriction, generally to <1.5 L/d• Primarily in inpatients due to need for:
– weight tracking (sign of diurnal water intake)– reinforcement schedules – close monitoring & re-direction– restraints & locked units in extreme cases
What was tried?
Date Intervention Results
Dec 28, 2011
Increased dose of olanzapine from 5 mg to 10 mg qHS to manage agitation
• no change• continued to require frequent
redirection/policing of fluid consumption
Jan 7, 2012
Added losartan 12.5 mg daily to olanzapine
• (as above) • agitation, anxiety and wandering
escalated required restraints
Jan 25,2012
Discontinued haloperidol • minimal improvement in parkinsonianmovements and water-seeking behaviour
Feb 29, 2012
Initiated quetiapine XR 50 mg qHS
• more calm and cooperative behaviour but minimal change in fluid intake
Ruling out other pharmacological options
Agent Limitations
Risperidone 2 case reports - Rao et al (2011), Kruse et al (2001)Required dose may worsen parkinsonian movements
Propranolol 2 case reports - Goldstein & Folsom (1991), Kathol et al (1986)
Demeclocycline 1 RCT (n=9) - Alexander et al (1991): early withdrawal and major AE (e.g. nephrotoxicity)Expensive and not available in Canada
Lithium Old case reportsAssociated with nephrotoxicity, thyrotoxicity
Enalapril, clonidine 1 non-randomized DB, PC cross-over trial - Greendyke et al (1998): no washout, no behavioural improvement
Naloxone 1 RCT (n=8) - Nishikawa et al (1996): inconclusive results
Conivaptan No studies
Is Clozapine Worth the Risk?
Generally well-tolerated in existing PPD literature low risk of agranulocytosis (<1%) and CSAN monitoring is mandatory average dose range over which benefit occurred was 150-300 mg/d,
which is well below where we expect seizures to occur
Hospital is the safest place to trial clozapine Potential for improved psychiatric symptoms, which may make K.R.
more consistently amenable to behavioural interventions K.R.’s low placement potential is primarily related to the need for 24
hr monitoring and fluid restriction social worker has already ruled out 7 appropriate facilities due to wait
lists and K.R.’s preferences more likely to find a site able/willing to do weekly CBC monitoring than
hourly Gatorade™ administration and constant behavioural redirection
04/07/2012
6
Therapeutic Plan
Continue fluid restriction to <1.5-2 L/d and other behavioural interventions (see next slide).
Perform baseline CBC. If WBC count ≥3500/mm3 and ANC ≥2000/mm3, start clozapine 12.5 mg PO once daily. initiate CSAN monitoring for agranulocytosis
Increase clozapine dose by 25-50 mg/d every 1-2 days if tolerated, to achieve lowest effective maintenance dose (divided BID-TID).
Once stabilized on clozapine, gradually taper and discontinue quetiapine if agitation is manageable.
Continue all other medications as ordered while hospitalized, and upon discharge.
If amenable to smoking cessation or required to abstain at facility, delay until after stabilized on clozapine and consider dose reduction of 30-50% to avoid dose-related toxicities.
Behavioural Care Plan
Patient can have 1 styrofoam cup of Gatorade q1h when hourly rounds are being done. Watch her drink. Encourage patient to watch the clock and anticipate “on-the-hour” cup of
Gatorade. She can ONLY drink Gatorade on the hour.
Remove cup promptly. Do not leave any cups or drinking vessels in her room. Staff control cups.
Tell patient that she cannot have water. She may have all fluids on meal trays (V8).
Do not permit pt any type of fluid preparation for herself or others i.e. she should not make tea for others
Remove ALL cues around drinking. “If you drink water, it can kill you!” Verbally contract with her: “Do you promise you will not drink water?” Continue off-unit activity contracts (e.g. church service)
Monitoring – Efficacy
Parameter Target Frequency Duration By:
Daily fluid intake <1.5 L/d daily long-term All
Serum Na (& other electrolytes)
135-145 mEq/L (normal)
q 3 days long-term RPh, MD
Average diurnal weight gain
<1.2% daily long-term (expect ↓ by 2 wks)
All
24-hr urine volume <3 L daily (expect ↓ by 2 wks)
Need for isolation no occurrence daily long-term MD, RN
Symptoms of water intoxification (i.e. confusion, seizures)
no occurrence daily long-term All
Agitation, anxiety minimal daily long-term All
Monitoring – Safety
Parameter Target Frequency By:
Sedation minimal daily All
Constipation minimal daily All
Orthostatic hypotension
minimal daily All
Salivation minimal daily All
Weight gain <15 lbs/yr baseline then weekly All
FBG, HbA1c minimal from baseline
baseline, at 3 mos then annually
RPh, MD, RN
Lipid profile minimal from baseline
baseline, at 3 mos then annually
RPh, MD
Seizures no occurrence daily All
Cardiomyopathy no occurrence daily RPh, MD
Parameter Target Frequency Duration By:
Agranulocytosis WBC ≥ 3.5 x 109/mm3
ANC ≥ 2.0 x 109/mm3
weekly for first 6 mos, then every 2 wks
until at least 4 wks after day clozapine is discontinued
RPh, MD
CBC Results Action
• 2.0 x 109/L ≤ WBC ≤ 3.5 x 109/L• 1.5 x 109/L ≤ ANC ≤ 2.0 x 109/L• flu-like complaints• fever• single fall or sum of falls in WBC ≥
3.0 x 109/L in last 4 wks, reaching < 4.0 x 109/L
• single fall or sum of falls in ANC ≥ 1.5 x 109/L in last 4 wks, reaching < 2.5 x 109/L
• Monitor twice-a-week.• Continue to dispense.• When pt returns to Green status, twice-
weekly monitoring is no longer required.
• WBC < 2.o x 109/L• ANC < 1.5 x 109/L
• Confirm lab results by drawing another sample within 24 hrs
• STOP clozapine immediately if results confirmed. Monitor for 4 wks.
• Clozapine therapy should not be resumed.
Conclusion
Psychogenic polydipsia is an under-recognized and underdiagnosed condition that is uncommon but can result in hospitalization or mortality.
Clozapine is the pharmacological option with the most evidence of benefit for water-drinking behaviour and psychosis in both schizophrenic and non-schizophrenic cases.
Clozapine is not required in most cases but is promising in patients in whom fluid restriction and other behavioural interventions are not enough.
04/07/2012
7
- W.C. Fields (1880-1946)
QUESTIONS?
“I never drink water. I'm afraid it will become habit-forming.”
References
Alexander RC et al. A double blind, placebo-controlled trial of demeclocyline treatment of polydipsia-hyponatremia in chronically psychotic patients. Biol Psychiatry. 1991;30:417-420.
Bersani G et al. Atypical antipsychotics and polydipsia: a cause or a treatment? 2007;22:103-107.
Canuso CM & Goldman MB. Clozapine restores water balance in schizophrenic patients with polydipsia-hyponatremia syndrome. Journal of Neuropsychiatry & Clinical Neurosciences. 1999;11(1):86-90.
de Leon, J et al. Treatment of polydipsia and hyponatremia in psychiatric patients. Can clozapine be a new option? Neuropsychopharmacology. 1995;12(2): 133-138.
de Leon J. Polydipsia: a study in a long-term psychiatric unit. Eur Arch Psychiatry Clin Neurosci. 2003;253:37-39.
Dundas B et al. Psychogenic polydipsia review: etiology, differential, and treatment. Current Psychiatry Reports. 2007;9(3):236-241.
Fuller MA et al. Clozapine reduces water-drinking behaviour in schizophrenic patients with polydipsia. 1996;16(4):329-332.
Greendyke RM et al. Polydipsia in chronic psychiatric patients: therapeutic trials of clonidine and enalapril. Neuropsychopharmacology. 1998;18:272-281.
References
Kruse D et al. Treatment of psychogenic polydipsia: comparison of risperidone and olanzapine, and the effects of an adjunctive angiotensin-II receptor blocking drug (irbesartan). Aust N Z J Psychiatry. 2001;35:65-68.
Leadbetter RA, Shutty MS Jr. Differential effects of neuroleptic and clozapine on polydipsiaand intermittent hyponatremia. J Clin Psychiatry. 1994;55(suppl B):110-113.
Lee HS, Kwon KY, Alphs LD, et al. Effect of clozapine on psychogenic polydipsia in chronic schizophrenia. J Clin Psychopharmacol. 1991;11:222-223.
Lowe & Ackman. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Annals of Pharmacotherapy. 2010;44(4):727-732.
Margetic B et al. Successful treatment of polydipsia, water intoxication, and delusional jealousy in an alcohol dependent patient with clozapine. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2006;30:1347-1349.
Mauri MC et al. Efficacy of clozapine in a non-schizophrenic patient with psychogenic polydipsia and central pontine myelinolysis. Hum Psychopharmacol Clin Exp. 2002;17:253-255.
Wicki J, Rutschmann OT, Burri H, et al. Rhabdomyolysis after correction of hyponatremia due to psychogenic polydipsia possibly complicated by clozapine. Ann Pharmacother. 1998;32:892-895.
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M A R I A Z H A N G
B S C P H M / P H A R M D S T U D E N T
J U L Y 4 , 2 0 1 2
Thinking outside the vial:When pills alone are not enough
OUTLINE
Patient case presentation
Brief background on Bipolar Disorder (BD) I and II
Indications, procedure and adverse events associated with electroconvulsive therapy (ECT)
Pharmacist’s role in managing patients experiencing a depressive episode of BD II
Clinical question and answer
Plan for patient based on current progress
JLM
33 year old obese, homosexual male
Presented in ER on April 24, 2012 with decreased LOC
Brought in by EMS after he was found unresponsive in a planter at Ryerson
No smell of ethanol
BG of 6.1
Urinalysis: + for amphetamines, benzodiazepines
Primary diagnosis: intentional suicide attempt by overdose of Seroquel 200mg x 15 tablets
JLM
Previous admissions to St. Michael’s:
December 2011: 3 month history of worsening symptoms of depression and plan to overdose Increased substance use involving crystal meth, THC, ecstasy
Dx: BD II depressive episode, THC, methamphetamine dependence
Discharged after 1 month admission
JLM
Family history
Father: alcohol dependence; was physically and psychologically abusive to mother and brother when intoxicated
Mother: multiple suicide attempts and hospitalizations
JLM
Medical history
Axis I: BD II depressed phase, cannabis dependence, polysubstance abuse; R/O’d major depressive episode and substance-induced disorder
Axis II: “cluster B” personality traits
Axis III: asthma, HIV+ (CD4 in December 2011: 436)
Axis IV: stressful relationships with family
Axis V: 30
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BIPOLAR DISORDER
Bipolar disorder: chronic, episodic mood disorder characterized by mood changes which impact function
Mania: elevated, expansive, or irritable mood x 1 week + 3 Sx including increased self esteem, decreased need for sleep, talkative, distractibility, racing thoughts etc. and are not due to direct physiological effects of a substance (stimulants, amphetamines, cocaine, etc.) or a general medical condition (hyperthyroidism)
BIPOLAR DISORDER
Hypomania: similar to manic episode but timeframe reduced to 4 days; episode is not severe enough to cause significant functional impairment
Depression: at least 5 of the following symptoms, one of which must be depressed mood or loss of interest for at least 2 weeks Depressed mood, loss of interest, change in appetite, change
in sleep, psychomotor retardation or agitation, loss of energy, feelings of worthlessness or inappropriate guilt, difficulty concentrating or indecisiveness, recurrent thoughts of death
BIPOLAR DISORDER IBIPOLAR DISORDER I BIPOLAR DISORDER IIBIPOLAR DISORDER II
Lifetime prevalence of ~1%
Def’n: at least one manic episode +/-depressive episodes
Lifetime prevalence of 1.1% Def’n: at least one
hypomanic episode + one or more depressive episodes; never had a full manic episode
Pts spend 40% more time in depressive state vs. BD I pts (greater proportion and higher frequency)
BIPOLAR DISORDER JLM
Past Medication history Citalopram 20mg daily Adderall 25mg daily Quetiapine 200mg PO qhs Zopiclone 7.5mg PO qhs Lorazepam 1mg PO prn
Allergies/intolerances Medications: Amoxicillin, aspirin, erythromycin,
penicillin, sulpha Other: bee sting
CANMAT GUIDELINES (2009) – ACUTETREATMENT
CANMAT GUIDELINES (2009) –MAINTENANCE TREATMENT
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MEDICATIONS IN HOSPITAL
Quetiapine 450mg po qhs Sertraline 200mg po daily Adderall XR 25mg qam Trazodone 100mg po qhs Clonazepam 1mg qhs Lorazepam 1mg PO qhs Prazosin 4mg po qhs Advair 250/25mcg 2 INH BID Ranitidine 150mg po daily Docusate sodium 100mg daily Psyllium 15g daily
So how was JLM doing?
April 24: admitted
May 22: minimal response to current medications, patient reported longstanding lack of response to most medications
May 31: discussed with MD re: possibility of receiving ECT, discussed options of unilateral or bilateral ECT, and the need to hold benzodiazepines the night before ECT; planned to start ECT in 1 week
ECT – INDICATIONS
Major Depressive Episode* Mania Schizophrenia
• Acute suicidality w/ high risk of acting on suicidal thoughts
• Psychotic features• History of poor response to
meds• History of good response to ECT• Catatonia• Risk of std antidepressant tx
outweigh risks of ECT (ex: in medically fail or elderly pts)
• Rapidly deteriorating physical status due to complications from depression (ex: poor PO intake)
• Patient preference
+• In the
presence of extreme and sustained agitation
• In the presence of manic delirium
Following are associated w/ favourable response to ECT• Catatonia• History of
good response
• Positive sxw/ abrupt or recent onset
ECT – PROCEDURE
Patient is sedated with general anesthesia and paralyzed with a muscle relaxant
Anesthesiologist is present to monitor RR, HR and BP during the procedure which is conducted by a psychiatrist
Electrodes are placed at precise locations on the head
Through electrodes, electric current passes through the brain to cause a seizure
AEs: HA, upset stomach, amnesia (anterograde and retrograde)
ECT – MEDICATIONS
DRUG INDICATION DOSE AEs
Methohexital Rapid-acting anaesthetic
0.5 –1.0mg/kg
Depressesseizure activity
Succinylcholine Paralyzing agent/muscle relaxant – prevent myalgias, bone fractures and dislocations
0.75 –1.5mg/kg
Myalgias, hyperthermia, hyperkalemia
Nitroglycerin Control CV responses– attenuates acute hypertensive response post-ECT stimulus
3mcg/kg IV Hypotension, bradycardia, headache
Esmolol 2mg/kg IV
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CLINICAL QUESTION
In patients with bipolar disorder II, after a good response to ECT, will they do better on
antidepressants + ECT, ECT alone or antidepressants alone?
P: bipolar disorder
I: ECT + antidepressants
C: ECT or antidepressant monotherapy
O: survival, hospitalizations etc.
Efficacy of Continuation ECT and Antidepressant Drugs Compared to Long-Term Antidepressants in Depressed Patients
Am J Psychiatry 2000; 157 :1960 – 1965
Objective Evaluate the efficacy of continuation ECT in depression
Method Continuation ECT group: retrospective review to identify 29 patients who received continuation ECT + long-term antidepressant tx after a positive response to acute treatment w/ ECT for a depressive episodeAntidepressant alone group: retrospective case-controlled approach was used to ascertain a matching group of 29 patients who received antidepressant treatment alone after responding positively to acute ECT
Patients N = 58; 46 w/ unipolar depression, 12 with bipolar disorder All were chronically depressed before receiving acute ECT; > 97% Caucasian, >83% female, >40% had family history of depressionBalanced groups; greater # of previous adequate antidepressant trials in continuation ECT groups (depressive Sx are more refractory to pharmacotx?)
Results Mean duration of F/U: 3.9 yrs; 5.4 yrs for continuation ECT pts and 2.4 yrs for antidepressants
Outcomes Cumulative probability of surviving w/o relapse or recurrence at 2 yrs: 93% for continuation ECT patients and 52% for antidepressant-alone patients Cumulative probability of surviving w/o relapse or recurrence at 5 yrs: 73% for continuation ECT ptsand 18% for antidepressant-alone patients Mean survival times: 6.9 yrs for continuation ECT patients and 2.7 years for antidepressant-alone patients
Conclusions Evidence for efficacy of continuing ECT + long-term antidepressant treatment in preventing relapse and recurrence in chronically depressed pts who have responded to acute treatment with ECT
Efficacy of Continuation ECT and Antidepressant Drugs Compared to Long-Term Antidepressants in Depressed Patients
Am J Psychiatry 2000; 157 :1960 – 1965
STRENGTHSSTRENGTHS LIMITATIONSLIMITATIONS
Preceding published literature on continuation ECT mainly consisted of case reports, naturalistic studies and retrospective case series of pts who clearly obtained benefit from continuation ECT
Large sample size (relatively)
Conducted in 2000 at 1 site (standards of practice have changed)
~28% had unilateral electrode placement
Mean age of pts were >62 years old
Small proportion of the group had BD I/II (<30%)
Selected patients who had positive response to acute ECT
Lack of objective measure to assess initial severity of depression and monitoring response
STRENGTHS & LIMITATIONS
So how is JLM doing?
June 15: no suicidal ideation x 1 week Brighter mood w/ antidepressants , ECT, ward environment and
Seroquel More future oriented and can envision leaving the hospital and
continuing ECT as an outpatient Didn’t want to be voluntary – pt believed that if he was let out, he
may attempt suicide
June 25: better at tolerating passes, no active suicidal ideation, fleeting thoughts of overdosing on OTCs when passing pharmacies
June 26: worried about going on an overnight pass; wondered if he could handle seeing his family after 2 months had passed In group, expressed that he was distressed about the possibility of
being discharged, felt he wasn’t ready to leave the hospital and didn’t want to be discharged without a psychiatrist
PLAN
Continue with current medications (quetiapine 450mg qhs, sertraline 200mg etc)
Continue with maintenance ECT Reassess indications of medications especially Adderall
XR because it may be contributing to anxiety Redo viral load and assess patient readiness to start
cART Increase in number of passes, give “voluntary status” and
prepare for discharge Connect patient with outpatient psychiatrist and
community supports
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MONITORING
Intervention Efficacy AEs
Quetiapine • Decrease thoughts of suicide
• Prevent suicide• Increase quality
of life• Prevent
depressive and hypomanic episodes
Weight gain, dizziness, dry mouth, headache, constipation, dyslipidemia, diabetes
Sertraline N/V/D, ejaculation disorder,excess perspiration, agitation, insomnia or somnolence
ECT Jaw pain, loss of recent memory or difficulty concentrating; usually dissipates within 1-2 weeks of ECT and may be confused with Sx of depression
TAKE HOME MESSAGES
Some patients experiencing a depressive episode of BD II may benefit from antidepressants and non-pharmacological interventions including ECT
It is crucial to individualize therapy in patients with mental illnesses
Psychosocial, socioeconomic and other illnesses including personality disorders may complicate and hinder recovery
QUESTIONS?
Thank you!REFERENCES
BC Ministry of Health Services & Mental Health Evaluation and Community Consultation Unit. Electroconvulsive Therapy: Guidelines for health authorities in British Columbia.
CANMAT. Depression: Treatment ECT. www.canmat.org/di-depression-treatment-ect.php
CANMAT. CANMAT and ISBD collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disorders 2009: 11: 225 – 255.
Ding, Z and White P. Anesthesia for Electroconvulsive Therapy. Anesthesia and Analgesia. 2002;94:1351-64.
National Institute of Health (NIH). Brain Stimulation Therapies.
04/07/2012
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The Role of Dual ASA and Clopidogrel Therapy in Secondary Stroke Prevention for Patients with Vertebrobasilar Atherosclerosis
Tiffany Kan
BScPhm/PharmD Candidate 2013
Leslie Dan Faculty of Pharmacy
University of Toronto
July 4, 2012
Outline
• Patient case presentation
• Overview of the pathophysiology of stroke
• Clinical question
• Critical appraisal of evidence
• Treatment plan and monitoring
Meet Mr. FR
• 87 year old male (78kg, 173cm)
• Chief complaint:▫ Development of dysphagia, slurred speech and right hand weakness
History of Presenting Illness
• May 28, 2012 (1600): Brought to ED by EMS
▫ Came from St. John’s Rehab
▫ Apparently well in the morning
▫ Around lunchtime, patient developed dysphagia, chewing difficulties, slurred speech and right hand weakness
▫ Speech progressively worsened to the point of aphasia while in ED
Past Medical History and Medications
Medical condition Medications on admission
Recent stroke (May 14, 2012)• Dx: right pontine infarct• 70% stenosis of left internal carotid artery (asymptomatic)
• Residual left‐sided weakness and gaitinstability
• Discharged May 24 to St. John’s Rehab
Clopidogrel 75mg od
Relevant past medication:ASA 81mg od (discontinued May 14)
Type 2 diabetes mellituswith mild nephropathy
Metformin 500mg odInsulin glargine 17 units qhs
Hypertension Amlodipine 10mg od
Hypercholesterolemia Atorvastatin 20mg od
Mr. FR
• Allergies: NKDA
• Social history: Lives at home with wife Independent with ADLs prior to first CVA Non‐smoker Non‐drinker
• Family history: Father suffered from stroke at age 60
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Physical ExaminationSystem Findings
Neuro Awake, alert, oriented x 3No obvious facial droopNormal extraocular movementsTongue deviated towards right; very slow tongue and uvula movementsDysarthric and dysphasicMild pronator drift on left sideMild residual left arm weakness, mild right hand weaknessDowngoing plantar response on right and left sideActivities involving coordination were slowed
HEENT T 37.2°C; unremarkable
Resp SaO2 95% on room air; unremarkable
CV BP 161/53, HR 80 bpm; unremarkable
GI/Hepatic Unremarkable
GU Unremarkable
Endo Unremarkable
Derm Unremarkable
Laboratory Investigations
System Parameter Value
Lytes Na 139 mmol/L
K 4.5 mmol/L
Cl 104 mmol/L
CV CK 82 umol/L
TnT 0.02 ug/L
Renal SCr 112 umol/L
CrCl 38 ml/min
System Parameter Value
Heme Hb 126 g/L
WBC 8.2 x 109/L
Plt 252 x 103/L
INR 1.07
aPTT 28.5 s
Endo FBG 6.1 mmol/L
A1C 7.8%
LDL (May14) 2.42 mmol/L
Diagnostic Imaging
Date Imaging Interpretation
May 28 CT Head • Stable right pontine infarct• No evidence of hemorrhagic transformation or acute ischemic injury
May 29 MRI Head • Development of left pontine infarct
May 30 CTA (Circle of Willis, Neck)
• Atherosclerotic stenosis of distal left vertebral artery (50% stenosis)
• Mild atherosclerotic stenosis of basilar artery• Hypoplastic right vertebral artery, atretic distally• Atherosclerotic stenosis of left proximal internal carotid artery (76% stenosis)
May 15 (first CVA)
Carotid Doppler Ultrasound
• 70% stenosis of left internal carotid artery
Cardiovascular Investigations
Date Imaging Findings
May 28 ECG • Normal sinus rhythm
May 31 Holter monitor • Normal sinus rhythm
June 1 Echocardiogram • Normal left ventricular function• Mild left ventricular hypertrophy
Clinical Course
• May 28:▫ Did not receive tPA▫ Received one dose of ASA 160mg in ED
▫ Continued clopidogrel 75mg od
▫ Admitted to stroke unit
• May 31:▫ Initiated dual antiplatelet therapy with ASA 81mg odand clopidogrel 75mg od
Drug Therapy Problems
• Mr. FR is currently receiving dual ASA and clopidogrel therapy for secondary stroke prevention, which may increase bleeding risk without providing additional clinical benefit compared to other antiplatelet therapies
• Mr. FR is at risk of acute complications and stroke recurrence secondary to uncontrolled hypertension
• Mr. FR is at risk of stroke recurrence secondary to suboptimal control of diabetes mellitus
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Classification of Stroke
Stroke
Ischemic stroke(88%)
Cryptogenic stroke (30%)
Other causes (5%)
(e.g., dissection, prothromboticstates, arteritis)
Cardiogenicembolism (20%)
(atrial fibrillation, valve disease)
Penetrating artery disease (25%)
(lacunar infarcts)
Large artery atherosclerosis
(20%)
Primary hemorrhage
(12%)
Dx: left pontine infarct with vertebrobasilar atherosclerosis
Adapted from DiPiro et al., Pharmacotherapy: A Pathophysiological Approach, 8e
Arterial Supply to the Brain
Common carotid artery
Internal carotid artery
External carotid artery
Vertebral artery, extracranial
Vertebral artery, intracranial
Basilar artery
Posterior Circulation Anterior Circulation
www.bartleby.com/107/
Posterior Circulation Strokes
• 20% of ischemic brain events
• Can be caused by stenosis or occlusion of large aortic arch, neck and intracranial arteries (vertebral, basilar, posterior cerebral arteries)
Most commonly due to atherosclerosis, embolism and dissection
• Variable clinical presentation
Vertigo, ataxia, diplopia, dysarthria, dysphagia, weakness, numbness
Basilar artery
Vertebral artery
www.bartleby.com/107/
Antithrombotic Therapy for Secondary Stroke Prevention in Noncardioembolic Strokes
• AHA/ASA Guidelines for the Prevention of Stroke in Patients with Stroke or Transient Ischemic Attack (2011):
▫ For patients with noncardioembolic ischemic stroke, antiplatelet agents are recommended over oral anticoagulation for secondary stroke prevention
▫ ASA monotherapy, combination of ASA and extended‐release dipyridamole (ASA‐ERDP), and clopidogrel monotherapy are all appropriate options for initial therapy
▫ The addition of ASA to clopidogrel is not recommended for routine secondary prevention after ischemic stroke or TIA
Stroke 2011; 42:227‐276
Clinical Question• Is dual ASA and clopidogrel therapy an effective and safe alternative for secondary stroke prevention in patients with vertebrobasilar atherosclerosis?
PICO
P Recurrent stroke, vertebrobasilar atherosclerosis, failed ASA and clopidogreltherapy
I Dual ASA and clopidogrel therapy
C Other antithrombotic regimens(i.e., ASA monotherapy, clopidogrel monotherapy, ASA‐ERDP, anticoagulation)
O Stroke recurrence, mortality, bleeding complications
Rationale for Dual Antiplatelet Therapy
• Using agents with different mechanisms of action may provide a greater degree of platelet inhibition compared to antiplatelet monotherapy
• In cardiology, dual ASA and clopidogrel therapy has been shown to be more effective than ASA alone in certain settings (acute coronary syndromes, stenting)
J Am Coll Cardiol 2003; 41(4 Suppl S): 79S‐88S
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Literature Search
• Relevant studies were identified by searching Medline, Embase, and PubMed
• MeSH terms included: “cerebrovascular accident”, “stroke”, “vertebrobasilar insufficiency”, “vertebral artery stenosis”, “hemorrhage”, “anticoagulation”, “platelet aggregation inhibitors”, “acetylsalicylic acid” or “Aspirin”, “clopidogrel”, “dipyridamole”
• References from original research articles and guidelines were reviewed
• Limited search to systematic reviews, meta‐analyses, and randomized controlled trials (RCTs)
Evidence in Intracranial Atherosclerosis
• No RCTs that compare antithrombotic therapies specifically in patients with vertebrobasilar atherosclerosis
• However, there are RCTs conducted in patients with intracranial atherosclerosis (which includes vertebral and basilar artery stenosis)
WASID: Anticoagulation vs. Antiplatelet Therapy
• RCT, DB, PC, MC
• P: TIA/stroke within 90 days before randomization (n=569) 50‐99% stenosis of major intracranial artery (20% vertebral, 20% basilar)
• I:Warfarin, target INR 2.0‐3.0
• C: ASA 650mg bid
• O: Trial terminated early due to safety concerns No significant difference in primary endpoint (ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke)
Significantly increased mortality and major hemorrhage with warfarin
• Limitations: Two‐year risk of primary endpoint was 22% despite antithrombotic therapy Nonstandard, large dose of ASA
N Engl J Med 2005; 352:1305‐1316
SAMMPRIS:PTAS vs. Aggressive Medical Management
• RCT, MC
• P: TIA/stroke within 30 days before enrollment (n=451) 70‐99% stenosis of major intracranial artery (13% vertebral, 20% basilar)
• I: PTAS + aggressive medical management
• C: Aggressive medical management only ASA 325mg od + clopidogrel 75mg od x 90d, then ASA monotherapy indefinitely
Strict risk factor management
• O: Higher risk of stroke or death with PTAS (20% vs. 12.2%; P=0.009)
• Limitations: Are effects due to dual antiplatelet therapy or risk factor management?
Would patients with <70% stenosis have the same benefits?
N Engl J Med 2011; 365:993‐1003PTAS = percutaneous transluminal angioplasty and stenting
Comparison of Antiplatelet Therapies
• Antiplatelet therapies have not been compared in RCTs specifically in patients with symptomatic intracranial atherosclerosis, therefore optimal antiplatelet therapy is uncertain in these patients
• Extrapolate from studies that compared antiplatelet therapies in patients with noncardioembolic ischemic strokes of all subtypes
MATCH:Dual Antiplatelet Therapy vs. Clopidogrel
• RCT, DB, PC, MC
• P: Ischemic stroke/TIA within preceding 3 months, plus at least one additional vascular risk factor (n=7599)
• I: Clopidogrel 75mg od + ASA 75mg od
• C: Clopidogrel 75mg od
• O: Mean duration of follow‐up 3.5y
No significant difference in primary endpoint (ischemic stroke, MI, vascular death, rehospitalization for acute ischemic event)
Significantly higher risk of life‐threatening bleeding with dual antiplatelettherapy (3% vs. 1%, P<0.0001)
• Limitations:
Mean time to randomization was 26.5 days
Stroke subtype: >50% lacunar, 35% large‐artery atherothrombotic
Lancet 2004; 364:331‐337
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FASTER:Dual Antiplatelet Therapy vs. ASA
• RCT, DB, PC, MC
• P: Stroke/TIA within 24h of symptom onset (n=392)
• I: ASA 81mg od + Clopidogrel 75mg od
• C: ASA 81mg od
• O: Trial terminated early due to slow recruitment
No significant difference in 90‐day risk of stroke
Significantly greater risk of total bleeding with dual therapy
• Limitation: early study termination, underpowered
Lancet Neurol 2007; 6:961‐969
CHARISMA:Dual Antiplatelet Therapy vs. ASA
• RCT, DB, PC, MC
• P: Documented coronary disease, cerebrovascular disease, symptomatic PAD, or multiple atherothrombotic risk factors (n=16,603)
• I: Clopidogrel 75mg od + ASA 75‐162mg/d
• C: ASA 75‐162mg/d
• O:Median duration of follow‐up was 28 months
No significant difference in primary endpoint (MI, stroke, CV death) or severe bleeding risk
Subgroup analysis: significant reduction with dual therapy in patients with symptomatic vascular disease (RR 0.88; P=0.046)
• Limitation: heterogenous patient population
N Engl J Med 2006; 354:1706‐1717
CARESS & CLAIR:Dual Antiplatelet Therapy vs. ASA
• RCT, DB, MC
• P: Recently symptomatic ≥50% carotid stenosis (n~100) CLAIR included intracranial ICA and MCA stenosis
• I: Clopidogrel 75mg od + ASA 75mg od
• C: ASA 75mg od
• O: Significant reduction in proportion of patient who had positive microembolic signals on days 2 and 7 with dual antiplatelet therapy
• Limitations: surrogate outcome, short duration of follow‐up, generalizability
Circulation 2005; 111:2233‐2240Lancet Neurol 2010; 9:489‐497
Meta‐analysis:Dual vs Mono Antiplatelet Therapy in Acute Stroke
• Meta‐analysis of 12 RCTs
• P: Acute noncardioembolic ischemic stroke/TIA within 3 days of symptom onset (n=3766)
• I: Dual antiplatelet therapy (ASA+Clopidogrel, ASA‐ERDP)
• C: Antiplatelet monotherapy (ASA, clopidogrel, or dipyridamole alone)
• O: Primary outcome was stroke recurrence
Significant reduction in stroke recurrence with dual therapy (3.3% vs. 5.0%; P=0.02)
Nonsignificant trend to increased major bleeding risk with dual therapy (0.9% vs. 0.4%; P=0.10)
• Limitations: heterogeneity, statistical analysis
Stroke 2012; 43:1058‐1066
Bleeding Risk
• Pooled analysis of 13 RCTs that compared bleeding risk of secondary stroke prevention regimens for noncardioembolic strokes (n=87,205)
• Primary outcome: total and major bleeding rates
Figure 1. Mean total bleeding rates per year Figure 2. Mean major bleeding rates per year
Am J Cardiol 2009; 103:1107‐1112
Limitations of Current Literature
• Lack of RCTs comparing antiplatelet therapies specifically in patients with vertebrobasilar atherosclerosis
• Heterogenous patient population
• Mean age of patients in studies (approximately 65y)
• Lack of RCTs specifically in patients who experience recurrent stroke while on antiplatelet therapy (ASA‐failure or clopidogrel‐failure patients)
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Summary
• There is a lack of evidence to support the routine use of dual ASA and clopidogrel therapy in secondary stroke prevention (and specifically in vertebrobasilar atherosclerosis)
• Important to consider the bleeding risk of the patient Do the benefits outweigh the risks?
• Optimization of risk factor management is an important component of secondary stroke prevention
Back to Mr. FR
Goals of Therapy:• Reduce ongoing neurologic injury
• Prevent stroke recurrence
• Decrease mortality and long‐term disability
Parameter Degree of Change Timeframe
Stroke symptoms No progression;improvement
For duration of therapy
Blood pressure < 130/80 mmHg Within 1 month
LDL cholesterol < 2 mmol/L Within 1 month
A1C Maintain or < 7% Within 3 months
Assessment of Alternatives
• Drug therapy problem:
• Mr. FR is currently receiving dual ASA and clopidogrel therapy for secondary stroke prevention, which increases bleeding risk without providing additional clinical benefit compared to other antiplatelettherapies
• Mr. FR’s risk factors for bleeding:
• Older age (87y)
• Hypertension
• Diabetes mellitus
• Renal impairment
Assessment of Alternatives
Alternative Assessment
1. ASA + Clopidogrel
2. Anticoagulation
• These options were ruled out since they have not been shown to be superior to the other antiplatelet regimens (ASA, clopidogrel, ASA‐ERDP) in noncardioembolic stroke, however have demonstrated increased risk of bleeding
3. ASA
4. Clopidogrel
5. ASA‐ERDP
• All 3 alternatives are effective in reducing stroke recurrence, however there is a lack of evidence to conclude that one agent is superior to the others
• Considering that FR experienced strokes while on ASA monotherapy and clopidogrel monotherapy, ASA‐ERDP is the most appropriate alternative
Therapeutic Plan
• Antithrombotic therapy Discontinue ASA and clopidogrel
Initiate ASA‐ERDP 25mg/200mg bid
• Optimize risk factor management
▫ Hypertension: Initiate perindopril 4mg od and indapamide 2.5mg od
Continue amlodipine 10mg od
▫ Diabetes mellitus: Increase metformin dose to 500mg bid
Continue insulin glargine 17 units qhs
▫ Hypercholesterolemia: Continue atorvastatin 20mg od
Monitoring: Efficacy EndpointsParameter Degree of Change Timeframe Who Monitors
Current stroke symptoms(dysphagia, dysarthria,right‐hand weakness)
No further worsening; improvement
For duration of tx MD, RN, RPh, patient
Stroke recurrence(symptoms of acute stroke)
Prevent For duration of tx MD, RN, RPh,patient
Blood pressure <130/80 mmHg Every 3 months MD, RN, RPh
A1C < 7.0% Every 6 months MD, RPh
FBG 4‐7 mmol/L Daily RN, patient
LDL < 2 mmol/L Every 3‐6 months MD, RPh
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Monitoring: Safety EndpointsParameter Degree of Change Timeframe Who Monitors
CNS: Headache Prevent For duration of tx MD, RPh, patient
CV: BP BP not <90/60 mmHg For duration of tx MD, RN, RPh
GI: NVD, abdominal pain, melena, hemoptysis
Prevent For duration of tx MD, RN, RPh, patient
Hepatic: liver enzymes Maintain WNL For duration of tx MD, RPh
Renal/GU: SCr, CrCl, hematuria
Maintain baseline SCrPrevent hematuria
For duration of tx MD, RPh
Endocrine: FBG, symptoms of hypoglycemia
FBG not <4 mmol/L Prevent hypoglycemia
For duration of tx MD, RN, RPh, patient
MSK: myalgia Prevent For duration of tx MD, RN, patient
Derm: abnormal bruising Prevent For duration of tx MD, RN, patient
Heme: CBC Maintain baseline/WNL For duration of tx MD, RPh
Lytes: Na, K, Cl Maintain WNL For duration of tx MD, RPh
Outcomes• Mr. FR was continued on dual antiplatelet therapy with ASA 81mg od and clopidogrel 75mg od
• Interventions were initiated to optimize risk factor management:
Initiated perindopril 4mg od and indapamide 2.5mg od
Increased metformin dose to 500mg bid
Continued atorvastatin 20mg od, amlodipine 10mg od, insulin glargine 17 units qhs
• Endovascular procedures (angioplasty and stenting) were considered inappropriate for Mr. FR due to unacceptable risk of mortality and morbidity
References• Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic
events. N Engl J Med 2006; 354:1706‐1717.
• Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365:993‐1003.
• Chimowitz MI, Lynn MJ, Howlett‐Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352:1305‐1315.
• Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemicstroke or transient ischaemic attack in high‐risk patients (MATCH): randomised, double‐blind, placebo‐controlled trial. Lancet 2004; 364:331‐337.
• Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline of healthcare professionals from the American Heart Association/American Stroke Association. Stroke2011; 42:227‐276.
• Geeganage CM, Diener HC, Algra A, et al. Dual or mono antiplatelet therapy for patients with acute ischemic stroke or transient ischemic attack: systematic review and meta‐analysis of randomized controlled trials. Stroke 2012; 43:1058‐1066.
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COLCHICINE IN ACUTE MYOPERICARDITIS
A CASE PRESENTATIONBY HEATHER BANNERMAN
JULY 4, 2012
Outline
• Case Presentation
• Pathophysiology, Diagnosis, and Standard Treatment of Myopericarditis and Pericarditis
• Therapeutic Question
• Literature Review
• Recommendation and Monitoring
Case Presentation
Mr.GF‐ 22yoMwithchestpain
• History of Presenting Illness• 4 day history of nausea, vomiting, and pleuritic chest pain. Chest pain became severe (10/10) on the day of admission.
• No SOB on exertion, but SOB with chest pain.
• Mentioned that some friends at school had upper respiratory tract infections earlier in the week.
• No recent travel.
• Past medical history insignificant
• No medications on admission
• No known drug allergies
Mr.GF‐ ReviewofSystemsBody System Characteristics/ Labs
CNS • Alert and oriented x 3• Neurologic screen normal
EENT • Mucous membranes moist
Respiratory • No cough, no phlegm• No SOB on exertion, but SOB with chest pain• RR= 18
Cardiovascular • No peripheral edema• Chest clear to auscultation/possible pericardial rub• Normal JVP• BP= 108/69, HR= 95, trop= 12.8, CK= 408• CXR= normal• ECG= NSR, diffuse ST elevation• 2D echo= global hypokinesis, LVEF 45%, “smoke” in the
left ventricle
Mr.GF‐ ReviewofSystemsBody System Characteristics/ Labs
GI/hepatic/renal • No abdominal distention• No organomegaly• Normal bowel sounds• Watery, loose, malodorous diarrhea with no
blood• Nausea, vomiting• AST= 69
Endocrine • Thyroid normal to touch
Derm • No rash, no arthralgias
Electrolytes • Normal
Immune/heme • Temp= 37.3• Plt= 75, INR= 1.2
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Mr.GF‐ DiagnosisandPlanDiagnosis‐Myopericarditis, possibly due to Coxsackie virus (enterovirus)
*
*couldn’t use ACEI for afterload reduction because of low resting blood pressure (his baseline)
Medication Goal
Indomethacin 50mg po tid Reduce inflammation/pain
Pantoprazole 40mg po daily GI protection
Heparin infusion Anticoagulation
Carvedilol 3.125mg po bid B blockade to reduce work on the heart
PRN medications included nitrospray, senna, milk of magnesia, gravol, zopiclone, acetaminophen and morphine
Mr.GF‐ HospitalCourse• Day 2
• N/V/D resolved.
• Chest pain significantly decreased.
• HR= 109, trop normalizing. BB dose increased to 3.125mg poq8h.
• Day 3
• HR= 109, BB dose increased to 6.25mg po bid.
• Day 4
• HR= 70.
• Day 6
• 2D echo‐ LVEF normal, with no swirling of blood in the ventricle.
• ECG‐ no new changes.
• Heparin infusion was stopped.
Pathophysiology, Diagnosis, and Standard Treatment of
Myopericarditis and Pericarditis
Pericarditis
• Inflammation
of the pericardium
due to viral,
metabolic,
autoimmune,
neoplastic, or
trauma‐related (cardiac surgery) causes10.
• Accounts for 5% of patients presenting to the emergency department with chest pain10.
• Can be acute, recurrent, or chronic.
Pericarditis
• Etiology• Viruses are the most common etiologic agent (30‐50%). The inflammation can be due to viral attack, immune response, or both11.
• Epidemiology• Based on the etiology of the pericarditis.• Coxsackie virus is an enterovirus which is most prevalent during summer and fall9.
• Myocardial involvement (ie. myopericarditis)‐younger and male9.
Diagnosis
• Based on the presence of ≥2 of the following10, 11:
• Pleuritic chest pain.
• Pericardial friction rub on auscultation.
• Widespread ST‐segment elevation on ECG.
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Myopericarditis=Pericarditis+elevatedtroponin
• Spectrum of myopericardial inflammatory syndromes with same etiologic agents.
• Mixed myocardial and pericardial involvement present in most cases8.
• Myopericarditis should generally be treated as pericarditis, as long as there is a preserved or only mildly reduced left ventricular ejection fraction (ie 45‐50%)8.
GoalsofTherapy
• Main goals of therapy: decrease pain, decrease inflammation, prevent recurrence.
• Recurrence is a very common and troublesome complication of acute pericarditis, occurring in 10‐30% of patients with a first episode of acute pericarditis.
• After a first recurrence, the likelihood of having subsequent recurrences can be up to 50%4.
StandardTreatment
• European Society of Cardiology 2004 Guidelines11:• NSAIDS are mainstay but use of NSAID should be evaluated against the degree of myocardial involvement. In clinical practice, lower NSAID doses are used and for a shorter period of time in myopericarditis, depending on degree of myocardial involvement9,11.
• GI protection must be provided.
• Only use corticosteroids if NSAIDs are contraindicated8,11.
• Colchicine is an option in addition to NSAID therapy to reduce the rate of recurrence of pericarditis, but poor quality of evidence to support its use.
Howdoescolchicinework?
• Not fully understood.• Colchicine inhibits microtubule self‐assembly.
• Concentrates in leukocytes and interferes with motility and phagocytosis6.
REDUCES INFLAMMATORY RESPONSE
Backtothecase…
Drug Therapy Problem
FG is at risk of recurrent episodes of myopericarditis and requires additional
drug therapy.
Therapeutic Question
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Does the addition of colchicine to standard NSAID therapy reduce recurrences in patients with a first episode of acute myopericarditis?
• P: patients with acute myopericarditis (first episode)
• I: colchicine + NSAID
• C: NSAID
• O: reduce recurrences of pericarditis
Literature Review
LiteratureSearch
• Pubmed, Embase searches using keywords “colchicine” + “myopericarditis” OR “pericarditis”.
• Reviewed articles referenced in the European Society of Cardiology 2004 Guidelines11.
Evidencepriorto2004
• Case reports and Case series
• Guindo et al1 (1997)
• Design: case series
• Type of prevention: secondary (recurrent pericarditis)
• Patients:• N=51, mean age 40.8 years, idiopathic pericarditis in 33 patients
• Follow up‐mean 36 months.
• 13.7% had recurrences with colchicine treatment.
• Symptom free periods before vs after colchicine treatment SIG (3.1 versus 43.0 months; P<0.0001).
Evidenceafter2004
• Randomized trials
1. CORE (2005)‐ COlchicine for REcurrentpericarditis.
2. COPE (2005)‐ COlchicine for acute PEricarditis.
3. CORP (2011)‐ COlchicine for Recurrent Pericarditis.
CORE(2005)‐ Imazio etal.2• Design: Prospective, Randomized, Open label, single center
• Type of prevention: secondary (recurrent pericarditis)
• Patients:
• N= 84; mean age 54 years, first recurrence of pericarditis; 83% had previous idiopathic pericarditis.
• Intervention:
• ASA 800mg q6‐8h x 7‐10 days, then gradually taper over 3‐4 weeks *prednisone if ASA contraindicated*
• Colchicine 1mg bid x 1 day, then 0.5mg bid x 6 months (for pts<70kg, colchicine 1mg x 1, then 0.5mg per day).
• Comparator:
• ASA 800mg q6‐8h x 7‐10 days, then gradually taper over 3‐4 weeks *prednisone if ASA contraindicated*
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COREcontinued…• Outcomes:
• Primary endpoint= recurrence at 18mths
• Colchicine + ASA‐ 21%• ASA‐ 45%• P= 0.04
• Secondary= • symptom persistence
>72h decreased in
colchicine + ASA group,
adverse events not
different.
COPE(2005)‐ Imazio etal.3
• Design: Prospective, Randomized, Open label, two centers
• Type of prevention: secondary (after the first episode of pericarditis)
• Patients:
• N= 120; mean age 56.9 years, first episode of pericarditis.
• Intervention:
• ASA 800mg q6‐8h x 7‐10days, with gradual tapering over 3‐4 weeks. *prednisone if ASA contraindicated*
• Colchicine 1‐2mg on first day followed by 0.5‐1mg/d x 3 months (if <70kg, colchicine 0.5 mg/day).
• Comparator:
• ASA 800mg q6‐8h x 7‐10days, with gradual tapering over 3‐4 weeks. *prednisone if ASA contraindicated*
COPEcontinued…• Outcomes:
• Primary endpoint= recurrence at 18 months. • Colchicine + ASA‐ 10.4%• ASA‐ 32.3%• P= 0.004
• Secondary• Symptom persistence at 72hr decreased in colchicine + ASA group
• Side effect rates and rates of severe adverse events were not different
• GI intolerance was main side effect of colchicine
COPEcontinued…
• Comments:
• Patients with first episode of acute pericarditis.
• ½ had ST elevation.
• Corticosteroid use was not sig diff btw groups.
• 0 lost to follow up.
• 5 D/C colchicine due to diarrhea.
• Open label trial. However, validation of clinical events was ensured by an ad‐hoc committee of expert cardiologists blinded to patients’ treatment allocation.
CORP(2011)‐ Imazio etal.4
• Design: Prospective, Randomized, Double blinded, MC
• Type of prevention: secondary (recurrent pericarditis)
• Patients:
• N= 120; mean age 47.6 years, first recurrence of pericarditis; 81.5% had previous idiopathic pericarditis.
• Intervention:
• ASA 800‐1000mg (or 600mg ibuprofen) q8h x 7‐10 days, with gradual tapering over 3‐4 weeks.
• Colchicine 1‐2mg on first day followed by 0.5‐1mg/day x 6 months (if <70kg, colchicine 0.5 mg/day).
• Comparator:
• ASA 800‐1000mg (or 600mg ibuprofen) q8h x 7‐10days, with gradual tapering over 3‐4 weeks.
CORPcontinued…• Outcomes:
• Primary endpoint=
recurrence at 18 months.• Colchicine + ASA‐ 24%
• ASA‐ 55%
• P= <0.001
• Secondary
• Symptom persistence at 72 hrs
& remission rate in one week
were both sig decreased.
• Side effects and drug withdrawal rates were not different.
• GI intolerance was main side effect of colchicine.
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Meta‐analysis(2012)‐ Imazioetal.5
Metaanalysiscontinued…• Both primary and secondary prevention.
• Colchicine use was associated with a reduced risk of pericarditis during follow‐up. RR=0.40, p<0.001, p for heterogeneity=0.95, I2=0%.
• Colchicine use was associated with increased drug withdrawals.
• No increase in adverse events.
• GI intolerance was most frequent side effect (mean incidence‐ 8%).
Summaryofevidence
Strengths Weaknesses
No increases in adverse events
No double blind trial in first episode of pericarditis
Randomized trials Same author (Imazio)
Consistent positive results
No studies in myopericarditis
No long term data
No data for optimal duration of therapy
Recommendation and Monitoring
AssessmentofAlternatives
FOR COLCHICINE AGAINST COLCHICINE
Evidence suggests that it decreases recurrences
Optimal duration hasn’t been established
Safe (no increase in adverse events)
No evidence in myopericarditis
Short treatment duration (3 months)
No double blind studies for use of colchicine in first presentation of pericarditis
FG has good renal function GI side effects
FG had only minor myocardial involvement
TherapeuticPlanandOutcome
• Plan
• Recommended the addition of colchicine 0.5mg po bid x 1 day, followed by 0.5mg poonce daily (because GF is <70kg) x 3 months (from the COPE trial).
• Outcome
• MD discharged patient on a maintenance dose of colchicine 0.5mg po once daily x 3 months (in addition to ASA 81mg po daily and carvedilol 6.25mg po bid).
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Monitoring‐ EfficacyParameter Degree of
Change
Timeframe Frequency By who?
Chest pain Prevent For duration of therapy Daily Patient, Nurse
Fever Prevent For duration of therapy Daily Patient, Nurse
Pericardial
friction rub
Prevent For duration of therapy Upon chest
pain/fever
R. Ph, Nurse, MD
ECG changes Prevent For duration of therapy Upon chest
pain/fever
R. Ph, MD
Pericardial
effusion
Prevent For duration of therapy Upon chest
pain/fever
R. Ph, MD
WBC elevation Prevent For duration of therapy Upon chest
pain/fever
R. Ph, MD
ESR elevation Prevent For duration of therapy Upon chest
pain/fever
R. Ph, MD
C reactive protein
elevation
Prevent For duration of therapy Upon chest
pain/fever
R. Ph, MD
Troponin increase Prevent For duration of therapy Upon chest
pain/fever
R. Ph, MD
Monitoring‐ SafetyParameter Degree of
Change
Timeframe Frequency By who?
Abdominal pain/
cramping
Prevent For duration of therapy Daily Patient, Nurse
Nausea Prevent For duration of therapy Daily Patient, Nurse
Vomiting Prevent For duration of therapy Daily Patient, Nurse
Diarrhea Prevent For duration of therapy Daily Patient, Nurse
ALT increase Prevent For duration of therapy Monthly R. Ph, MD
AST increase Prevent For duration of therapy Monthly R. Ph, MD
Muscle pain Prevent For duration of therapy Daily Patient, Nurse
CK increase Prevent For duration of therapy Monthly and
upon muscle
pains
Patient, Nurse, R.
Ph, MD
References1. Guido J, Adler Y, Spodick DH, et al. Colchicine for recurrent pericarditis: 51 patients follow up for 10 years.
Circulation 1997; 96: 1‐29.
2. Imazio M, Bobbio M, Cecchi E, et al. Colchicine as first‐choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch Intern Med 2005; 165: 1987.
3. Imazio M, Bobbio M, Cecchi E, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005; 112(13): 2012.
4. Imazio M, Brucato A, Cemin R, et al. COlchicine for Recurrent Pericarditis. Ann Intern Med 2011; 155(7): 409‐14.
5. Imazio M, Brucato A, Forno D, et al. Efficacy and safety of colchicine for pericarditis prevention. Systematic review and meta‐analysis. Heart 2012; 98: 1078‐82.
6. Imazio M, Brucato A, Trinchero R, et al. Colchicine for pericarditis: hype or hope? European Heart Journal 2009; 30: 532‐539.
7. Imazio M, Cecchi E, Ierna S, et al. Investigation on Colchicine for Acute Pericarditis: a multicenter randomized placebo‐controlled trial evaluating the clinical benefits of colchicines as adjunct to conventional therapy in the treatment and prevention of pericarditis; study design and rationale. J Cardiovasc Med (Hagerstown) 2007; 8(8): 613‐7.
8. Imazio M, Spodick DH, Brucato A, et al. Controversial issues in the Management of Pericardial Diseases. Circulation 2010; 121: 916‐28.
9. Imazio M, Trinchero R. Myopericarditis: etiology, management, and prognosis. Int J Cardiol 2008; 127: 17‐26.
10. Kuo IF, Pearson GJ, Koshman, SL. Colchicine for the Primary and Secondary Prevention of Pericarditis: An update. The Annals of Pharmacotherapy 2009; 43: 2075‐81.
11. Maisch B, Seferovic PM, Ristic AD, et al. Guidelines on the diagnosis and management of pericardial diseases executive summary; The task force on the diagnosis and management of pericardial diseases of the European society of cardiology. Eur Heart J 2004; 25: 587‐610.
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