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Back to Basics Practical Pharmacology – part 3

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1 Back to Basics Practical Pharmacology – part 3
Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2013

2 Objectives List the 4 steps in rationalizing drug therapy choices using evidence based medicine. List the important parameters in choosing anti-thrombotic and psychiatric drugs in a clinical setting. Identify clinically important differences in the efficacy, toxicity, cost and convenience of these different drugs. Recognize the inherent weaknesses of current guidelines.

3 Topics Anti-Thrombotics Psychiatric Medications Anti-platelets
Anti-coagulants Psychiatric Medications Anti-depressants Anxiolytics Anti-psychotics

4 Oral Anti-Thrombotics
Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2013

5 Anti-Thrombotics From:

6 Oral Anti-thrombotics
Antiplatelets ASA ASA + Dipyridamole MR (Aggrenox®) Thienopyridines: Clopidogrel Ticlopidine Prasugrel Ticagrelor Anticoagulants Warfarin Dabigatran Rivaroxaban Apixaban adenosine diphosphate (ADP) receptors of subtype P2Y12 Ticagrelor – reversible inh – all others irrev Although ad hoc studies on their efficacy in the stroke prevention are currently lacking, newer antiplatelet agents (mainly ticagrelor and prasugrel) do not provide a significant better protection over and above aspirin and/or clopidogrel in the prevention of atherothrombotic stroke (PMID: )

7 Antiplatelets Indications Primary prevention MI
ASA Clopidogrel Ticlopidine Secondary prevention MI Prasugrel Ticagrelor Indications Primary prevention CVA ASA Clopidogrel Ticlopidine Secondary prevention CVA ASA + Dipyridamole MR

8 Mechanisms of Action ASA Irreversible inh of COX-1 Dipyridamole MR
(thromboxane reduction) Platelet lifespan: 7-10 days Dipyridamole MR inh the uptake of adenosine & breakdown of cGMP Ticagrelor Reversible inhibition of ADP platelet receptor subtype P2Y12 Thienopyridines Clopidogrel & Ticlopidine Prodrugs activated by P450-2C19 N.B. 2% - 14% of population are poor metabolizers Prasugrel Prodrug activated by ester bond hydrolysis via: Irreversible inhibition of ADP platelet receptor subtype P2Y12 Aggrenox -

9 How to Choose? (if only there was a process…)
Efficacy Toxicity Cost Convenience

10 Primary Prevention – MI & CVA
1) Efficacy (all ~ equivalent) ASA (++ evidence) 75mg = 325mg daily “For older patients with risk factors” CHEST’12: >50yrs consider risk vs benefit CCS’11: not recommended AHA’10: if 10yr CAD risk ≥10% USPSTF’09: men 45‐79 yrs if low bleed risk Diabetes: men≥45yr/women≥50yr; & ≥1 risk factor (smoking,↑BP, ↑ lipids, history of young parenteral MI, albuminuria) Clopidogrel & Ticlopidine Little direct evidence Only for ASA allergy or intolerance 2) Toxicity (bleeding ~ same) ASA NNH 125; major bleeds (WHS trial) Any GI bleed ~ 2.7% (severe 0.7%) Dyspepsia ~ 5% Clopidogrel (C) & Ticlopidine (T) Bleed: Any GI bleed 2% (severe 0.5%) (C) Rash: 6% (C) / 12% (3% severe) (T) TTP: >20/3 million (C) / >1/5000 (T) Neutropenia: <1% (C) / 2.4% (T) !! RISK FACTORS FOR BLEEDING: Age >75 yrs, DM, elevated INR warfarin, female, ↓ hematocrit, HF/MI, ↑HR, length of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke noncardioembolic, ↑Scr, ↓ wt. From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

11 Primary Prevention – MI & CVA
3) Cost ASA Pennies! 81mg costs > 325mg Can cut 325mg in 1/4th Clopidogrel ~ $95/mo Ticlopidine ~ $35/mo 4) Convenience ASA 75-325mg once daily Clopidogrel 75mg once daily Ticlopidine 250mg BID po Requires regular monitoring of CBC, LFTs 75mg – international study dose <80mg – legal limit in Canada – must sell behind the counter “baby” aspirin = Reyes syndrome risk in pediatric use >81mg – ok to sell OTC for CV indication Hence, 81mg tabs From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

12 Bottom Line – 1o Prevention MI & CVA
ASA. Most evidence, well tolerated, cheap cheap!, QD Consider bleed risks, even with “baby” ASA (81mg) RISK FACTORS FOR BLEEDING: Age >75 yrs, DM, elevated INR warfarin, female, ↓ hematocrit, HF/MI, ↑HR, length of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke noncardioembolic, ↑Scr, ↓ wt. Clopidogrel only if ASA allergic / severe intolerance Ignore ticlopidine: Little evidence, serious toxicities, BID dosing plus regular blood work! No evidence for Aggrenox® in primary prevention RISK FACTORS FOR BLEEDING: Age >75 yrs, DM, elevated INR warfarin, female, ↓ hematocrit, HF/MI, ↑HR, length of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke noncardioembolic, ↑Scr, ↓ wt. From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

13 Secondary Prevention – MI Efficacy
Agent Monotherapy Combo w/ ASA ASA Excellent evidence for NSTEMI, STEMI, CABG, PCI (low NNTs) -- Clopidogrel ~ equivalent to ASA (small absolute improvement per CAPRIE trial) Clopidogrel + ASA > ASA 3-12 mo (CURE trial)) (ACS, PCI various durations) Prasugrel untested Prasugrel + ASA > Clop + ASA (ACS + PCI) x12 mo (TRITON-TIMI 38 trial) Ticagrelor Ticagrelor + ASA > Clop + ASA (ACS + PCI +/- CABG) x12mo (PLATO trial) Aggrenox – same as clopidogrel in secondary prevention of MI –but this was only a secondary endpoint in the PRoFESS trial. Not reliable enough at present to use clinically. BUT: it shows that if using AGGRENOX for secondary prevention of CVA, don’t necessarily need extra ASA for cardioprotection, even though AGGRENOX has < 75mg of ASA in it. (thanks to the added effect of dipyridamole MR) From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013 From: Antiplatelet treatment Accessed Apr 4/13 From: Accessed Apr 4/13.

14 Secondary Prevention – MI Toxicity
Agent Monotherapy Combo w/ ASA ASA w/ ASA: rate of hemorrhagic events = 5.58 (95% CI, ) / 1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, ) Incidence rate ratio: 1.55; (95% CI, ) -- Clopidogrel Less GI bleed - clopidogrel < ASA (1.99% vs 2.66% p < 0.002) (Less severe GI bleed vs 0.71%; p < 0.05) Less GI events - clopidogrel < ASA (27.1 vs 29.8%; p < 0.001) More Diarrhea clopidogrel > ASA (4.46 vs 3.36%; p < 0.001) More Rash – clopidogrel > ASA (6.0% vs 4.6% p < 0.001) No difference in: Early D/C, Neutropenia, Thrombocytopenia & Intracranial bleed. (per CAPRIE) Major bleeding – clop + ASA > ASA (3.7% vs. 2.7%; RR = 1.38; P=0.001), Life-threatening bleeding - no diff (2.1 percent vs. 1.8 percent, P=0.13) Hemorrhagic strokes – no diff (per CURE trial) Prasugrel untested More fatal and life-threatening bleeds vs clopid + ASA Ticagrelor More major and minor bleeds vs clopid + ASA More dyspnea, & incr UA From: JAMA. 2012;307(21): Accessed Apr 4/13 From: CAPRIE trial: (see: “The incidence of early permanent discontinuations of the study drug due to adverse events was almost identical in both treatment groups (11.94% for clopidogrel vs 11.92% for aspirin). Reported neutropenia was similar in the clopidogrel and aspirin groups (0.10 vs 0.17%, respectively) with corresponding rates (0.05 vs 0.04%, respectively) for severe neutropenia. Thrombocytopenia was identical in the clopidogrel and aspirin groups (0.26%), with the rates of severe thrombocytopenia being 0.19 vs 0.10%, respectively. None of these observed differences was statistically significant. The overall incidence of haemorrhagic events did not differ statistically significantly between treatment groups (9.27% for clopidogrel vs 9.28% for aspirin; p = 0.98). There was a trend towards a lower incidence of intracranial haemorrhage in the clopidogrel group (0.31%) compared with the aspirin group (0.42%). Any reported gastrointestinal haemorrhage was significantly less frequent with clopidogrel (1.99%) than with aspirin (2.66%) [p < 0.002]. The corresponding data for severe gastrointestinal bleeding were 0.49 vs 0.71%; p < Overall, there were significantly fewer gastrointestinal adverse events with clopidogrel than with aspirin (27.1 vs 29.8%; p < 0.001), with less abdominal pain, dyspepsia, constipation, or peptic, gastric, or duodenal ulceration with clopidogrel. Diarrhoea was significantly more common in the clopidogrel group (4.46 vs 3.36%; p < 0.001), although the incidence of severe diarrhoea (0.23 vs 0.11%) was low and was not significantly different between groups. There were significantly more patients with rash in the clopidogrel group (6.0%) compared with the aspirin group (4.6%) [p < 0.001]. “ From: CURE Trial: - see Table 3 Frpm: “Prasugrel statistically significantly increased the rate of TIMI non-CABG major bleeding, which was reported in 2.4% of patients in the prasugrel group compared with 1.8% of patients in the clopidogrel group (HR 1.32; 95% CI 1.03 to 1.68, p = 0.03). Life-threatening bleeding occurred at a rate of 1.4% in the prasugrel group compared with 0.9% in the clopidogrel group (HR 1.52; 95% CI 1.08 to 2.13, p = 0.01), of which 0.4% were fatal in the prasugrel group and 0.1% in the clopidogrel group (HR 4.19; 95% CI 1.58 to 11.11, p = 0.002).” From: “Patients randomised to ticagrelor experienced more overall major and minor bleeding (HR 1.11; 95% CI 1.03 to 1.20;p = 0.008) as well as more major bleeding not related to CABG (HR 1.19; 95% CI 1.02 to 1.38;Page 6 of 45Copyright © NICE All rights reserved. Last modified October 2011Ticagrelor for the treatment of acute coronary syndromesNICE technology appraisal guidance 236p = 0.03). Intracranial bleeding was more common in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, with fatal intracranial bleeding statistically significantly more common in the ticagrelor plus aspirin group (HR not reported; p = 0.02). Fatal bleeding excluding intracranial bleeding was statistically significantly more common in the clopidogrel plus aspirin group (HR not reported; p = 0.03). There was no difference between the two groups in relation to overall fatal bleeding (0.3% in each group). Patients randomised to ticagrelor experienced dyspnoea statistically significantly more often than patients taking clopidogrel (13.8% versus 7.8% respectively; p < 0.001). More patients taking ticagrelor plus aspirin discontinued treatment because of dyspnoea than patients taking clopidogrel plus aspirin (0.9% versus 0.1% respectively; p < 0.001). Holter monitoring detected more ventricular pauses of3 seconds or longer during the first week in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, but these occurred infrequently at 30 days of treatment and were rarely associated with symptoms. Patients treated with ticagrelor had statistically significantly greater increases from baseline in levels of serum uric acid and serum creatinine compared with those on clopidogrel (p < for both events throughout the study).”

15 Secondary Prevention – MI Toxicity
Agent Monotherapy Combo w/ ASA ASA w/ ASA: rate of hemorrhagic events = 5.58 (95% CI, ) / 1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, ) Incidence rate ratio: 1.55; (95% CI, ) -- Clopidogrel ~ equivalent in absolute sense Slightly less GI bleed & GI events except diarrhea; More Rash More major bleeding vs ASA alone Prasugrel untested More fatal and life-threatening bleeds vs Clopid + ASA Ticagrelor More major and minor bleeds vs Clopid + ASA More dyspnea & increased urate From: JAMA. 2012;307(21): Accessed Apr 4/13 From: CAPRIE trial: (see: “The incidence of early permanent discontinuations of the study drug due to adverse events was almost identical in both treatment groups (11.94% for clopidogrel vs 11.92% for aspirin). Reported neutropenia was similar in the clopidogrel and aspirin groups (0.10 vs 0.17%, respectively) with corresponding rates (0.05 vs 0.04%, respectively) for severe neutropenia. Thrombocytopenia was identical in the clopidogrel and aspirin groups (0.26%), with the rates of severe thrombocytopenia being 0.19 vs 0.10%, respectively. None of these observed differences was statistically significant. The overall incidence of haemorrhagic events did not differ statistically significantly between treatment groups (9.27% for clopidogrel vs 9.28% for aspirin; p = 0.98). There was a trend towards a lower incidence of intracranial haemorrhage in the clopidogrel group (0.31%) compared with the aspirin group (0.42%). Any reported gastrointestinal haemorrhage was significantly less frequent with clopidogrel (1.99%) than with aspirin (2.66%) [p < 0.002]. The corresponding data for severe gastrointestinal bleeding were 0.49 vs 0.71%; p < Overall, there were significantly fewer gastrointestinal adverse events with clopidogrel than with aspirin (27.1 vs 29.8%; p < 0.001), with less abdominal pain, dyspepsia, constipation, or peptic, gastric, or duodenal ulceration with clopidogrel. Diarrhoea was significantly more common in the clopidogrel group (4.46 vs 3.36%; p < 0.001), although the incidence of severe diarrhoea (0.23 vs 0.11%) was low and was not significantly different between groups. There were significantly more patients with rash in the clopidogrel group (6.0%) compared with the aspirin group (4.6%) [p < 0.001]. “ From: CURE Trial: - see Table 3 Frpm: “Prasugrel statistically significantly increased the rate of TIMI non-CABG major bleeding, which was reported in 2.4% of patients in the prasugrel group compared with 1.8% of patients in the clopidogrel group (HR 1.32; 95% CI 1.03 to 1.68, p = 0.03). Life-threatening bleeding occurred at a rate of 1.4% in the prasugrel group compared with 0.9% in the clopidogrel group (HR 1.52; 95% CI 1.08 to 2.13, p = 0.01), of which 0.4% were fatal in the prasugrel group and 0.1% in the clopidogrel group (HR 4.19; 95% CI 1.58 to 11.11, p = 0.002).” From: “Patients randomised to ticagrelor experienced more overall major and minor bleeding (HR 1.11; 95% CI 1.03 to 1.20;p = 0.008) as well as more major bleeding not related to CABG (HR 1.19; 95% CI 1.02 to 1.38;Page 6 of 45Copyright © NICE All rights reserved. Last modified October 2011Ticagrelor for the treatment of acute coronary syndromesNICE technology appraisal guidance 236p = 0.03). Intracranial bleeding was more common in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, with fatal intracranial bleeding statistically significantly more common in the ticagrelor plus aspirin group (HR not reported; p = 0.02). Fatal bleeding excluding intracranial bleeding was statistically significantly more common in the clopidogrel plus aspirin group (HR not reported; p = 0.03). There was no difference between the two groups in relation to overall fatal bleeding (0.3% in each group). Patients randomised to ticagrelor experienced dyspnoea statistically significantly more often than patients taking clopidogrel (13.8% versus 7.8% respectively; p < 0.001). More patients taking ticagrelor plus aspirin discontinued treatment because of dyspnoea than patients taking clopidogrel plus aspirin (0.9% versus 0.1% respectively; p < 0.001). Holter monitoring detected more ventricular pauses of3 seconds or longer during the first week in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, but these occurred infrequently at 30 days of treatment and were rarely associated with symptoms. Patients treated with ticagrelor had statistically significantly greater increases from baseline in levels of serum uric acid and serum creatinine compared with those on clopidogrel (p < for both events throughout the study).”

16 Secondary Prevention – MI
3) Cost ASA Pennies! (only 325mg covered) Clopidogrel ~ $95/mo LU code for MI Prasugrel ~ $95/mo; not covered Ticagrelor ~ $105/mo; not covered 4) Convenience ASA 75-325mg once daily Clopidogrel 75mg once daily Prasugrel 10mg once daily Tigagrelor 90mg BID po 75mg – international study dose <80mg – legal limit in Canada – must sell behind the counter “baby” aspirin = Reyes syndrome risk in pediatric use >81mg – ok to sell OTC for CV indication Hence, 81mg tabs From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

17 Bottom Line: 2o Prevention MI
ASA + Clopidogrel x mo, then ASA alone Clopidogrel alone if ASA allergy Prasugrel only in cardiac centres post ACS + PCI & if no excess bleed risks

18 Secondary Prevention – CVA Efficacy
Agent Monotherapy Combo w/ ASA ASA ASA ~23% RRR > placebo NNT ~ x1 year to prevent any vascular event. (50-325mg) (CAST, IST, SALT, Dutch-TIA trials) -- Ticlopidine Superior to ASA (CATS & TASS trials) unknown Clopidogrel Equivalent to ASA (extremely small absolute improvement per CAPRIE trial) Possible improvement for 1st 21 days post CVA (CHANCE trial) No benefit long term (CHARISMA, MATCH trials) Aggrenox® Superior to ASA (ESPRIT & ESPS2 trials), but Equivalent to Clopidogrel (PRoFESS trial) whaa? CAPRIE trial: ASA 325mg vs Clopidogrel 75mg > pts! (1 in 3 had ischemic stroke) Ischemic stroke/MI/Vascular death 5.32%(CLOP) vs 5.83%(ASA) event rate/yr RRR = ~9%; ARR = 0.51; NNT = 196 Benefit seen only in multiple groups with multiple composite endpoints. No benefit of clopidrogel over ASA to reduce recurrent stroke events. Lancet 1996;348(9038): Aggrenox – same as clopidogrel in secondary prevention of MI –but this was only a secondary endpoint in the PRoFESS trial. Not reliable enough at present to use clinically. BUT: it shows that if using AGGRENOX for secondary prevention of CVA, don’t necessarily need extra ASA for cardioprotection, even though AGGRENOX has < 75mg of ASA in it. (thanks to the added effect of dipyridamole MR) From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013 From: Antiplatelet treatment Accessed Apr 4/13 From: Accessed Apr 4/13.

19 Secondary Prevention – CVA Toxicity
Agent Monotherapy Combo w/ ASA ASA Low, but look at additive bleeding risk factors: (Age >75 yrs, DM, elevated INR warfarin, female, ↓ hematocrit, HF/MI, ↑HR, length of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke noncardioembolic, ↑Scr, ↓ wt.) -- Clopidogrel ~ equivalent in absolute sense Slightly less GI bleed & GI events except diarrhea; More Rash More bleeding vs ASA alone (CHARISMA & MATCH trials) Aggrenox® More headache, diarrhea, GI upset, dizziness, & early D/C vs ASA or Clopidogrel More intracranial bleed vs Clopidogrel From: JAMA. 2012;307(21): Accessed Apr 4/13 From: CAPRIE trial: (see: “The incidence of early permanent discontinuations of the study drug due to adverse events was almost identical in both treatment groups (11.94% for clopidogrel vs 11.92% for aspirin). Reported neutropenia was similar in the clopidogrel and aspirin groups (0.10 vs 0.17%, respectively) with corresponding rates (0.05 vs 0.04%, respectively) for severe neutropenia. Thrombocytopenia was identical in the clopidogrel and aspirin groups (0.26%), with the rates of severe thrombocytopenia being 0.19 vs 0.10%, respectively. None of these observed differences was statistically significant. The overall incidence of haemorrhagic events did not differ statistically significantly between treatment groups (9.27% for clopidogrel vs 9.28% for aspirin; p = 0.98). There was a trend towards a lower incidence of intracranial haemorrhage in the clopidogrel group (0.31%) compared with the aspirin group (0.42%). Any reported gastrointestinal haemorrhage was significantly less frequent with clopidogrel (1.99%) than with aspirin (2.66%) [p < 0.002]. The corresponding data for severe gastrointestinal bleeding were 0.49 vs 0.71%; p < Overall, there were significantly fewer gastrointestinal adverse events with clopidogrel than with aspirin (27.1 vs 29.8%; p < 0.001), with less abdominal pain, dyspepsia, constipation, or peptic, gastric, or duodenal ulceration with clopidogrel. Diarrhoea was significantly more common in the clopidogrel group (4.46 vs 3.36%; p < 0.001), although the incidence of severe diarrhoea (0.23 vs 0.11%) was low and was not significantly different between groups. There were significantly more patients with rash in the clopidogrel group (6.0%) compared with the aspirin group (4.6%) [p < 0.001]. “ From: CURE Trial: - see Table 3 Frpm: “Prasugrel statistically significantly increased the rate of TIMI non-CABG major bleeding, which was reported in 2.4% of patients in the prasugrel group compared with 1.8% of patients in the clopidogrel group (HR 1.32; 95% CI 1.03 to 1.68, p = 0.03). Life-threatening bleeding occurred at a rate of 1.4% in the prasugrel group compared with 0.9% in the clopidogrel group (HR 1.52; 95% CI 1.08 to 2.13, p = 0.01), of which 0.4% were fatal in the prasugrel group and 0.1% in the clopidogrel group (HR 4.19; 95% CI 1.58 to 11.11, p = 0.002).” From: “Patients randomised to ticagrelor experienced more overall major and minor bleeding (HR 1.11; 95% CI 1.03 to 1.20;p = 0.008) as well as more major bleeding not related to CABG (HR 1.19; 95% CI 1.02 to 1.38;Page 6 of 45Copyright © NICE All rights reserved. Last modified October 2011Ticagrelor for the treatment of acute coronary syndromesNICE technology appraisal guidance 236p = 0.03). Intracranial bleeding was more common in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, with fatal intracranial bleeding statistically significantly more common in the ticagrelor plus aspirin group (HR not reported; p = 0.02). Fatal bleeding excluding intracranial bleeding was statistically significantly more common in the clopidogrel plus aspirin group (HR not reported; p = 0.03). There was no difference between the two groups in relation to overall fatal bleeding (0.3% in each group). Patients randomised to ticagrelor experienced dyspnoea statistically significantly more often than patients taking clopidogrel (13.8% versus 7.8% respectively; p < 0.001). More patients taking ticagrelor plus aspirin discontinued treatment because of dyspnoea than patients taking clopidogrel plus aspirin (0.9% versus 0.1% respectively; p < 0.001). Holter monitoring detected more ventricular pauses of3 seconds or longer during the first week in the ticagrelor plus aspirin group than in the clopidogrel plus aspirin group, but these occurred infrequently at 30 days of treatment and were rarely associated with symptoms. Patients treated with ticagrelor had statistically significantly greater increases from baseline in levels of serum uric acid and serum creatinine compared with those on clopidogrel (p < for both events throughout the study).”

20 Secondary Prevention – CVA
3) Cost ASA Pennies! Clopidogrel ~ $95/mo LU code for ASA intolerance only Aggrenox® ~ $61/mo LU code for CVA 4) Convenience ASA 75-325mg once daily Clopidogrel 75mg once daily Aggrenox® 200/25mg BID po 75mg – international study dose <80mg – legal limit in Canada – must sell behind the counter “baby” aspirin = Reyes syndrome risk in pediatric use >81mg – ok to sell OTC for CV indication Hence, 81mg tabs From: ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

21 Bottom Line 2o Prevention CVA
ASA or Clopidogrel or Aggrenox® Any will do, until tie breaker trial between these agents. Aggrenox® might be more efficacious, but with more side effects and less convenience.

22 Anticoagulants Rivaroxaban Apixaban Warfarin Factor Xa inhibitor
Vitamin K antagonist (clotting factors 2,7,9,10, protein C & S) For: Afib, VTE prophylaxis & tx, valvular disease Dabigatran Direct thrombin inhibitor (factor 2) For: Afib, VTE prophylaxis post-op TKR/THA (N.B. Ximelagatran – withdrawan due to hepatotoxicity) Rivaroxaban Factor Xa inhibitor For: Afib, VTE prophylaxis post-op TKR/THA, DVT tx Apixaban For: Afib, VTE prophylaxis post-op TKR/THA

23 Anticoagulants (VTE, Afib, Valve disease)
Agent Efficacy Toxicity Warfarin Excellent vs placebo or ASA 1.3% - 3.5% -- major bleed < 0.25% - 0.5%/yr -- ICH Dabigatran ~ same N.B. (~1% absolute difference) (RE-LY trial - industry funded) Less intracranial & More GI bleeds; ?More MI? Untested > 79y.o. or CrCL < 30 NO reversal agent Rivaroxaban N.B. (<1% absolute difference) (ROCKET-AF trial – industry funded) Less intracranial & More GI bleeds Apixaban (ARISTOTLE trial – industry funded) Less intracranial bleeds GI bleeding – no difference Untested > 77y.o. or CrCL < 30 Rivaroxaban: Dabigatran: Apixaban:http://www.rxfiles.ca.proxy.bib.uottawa.ca/rxfiles/uploads/documents/ARISTOTLE-AF-Apixaban.pdf All:

24 Rxfiles.ca Comparison of Warfarin & New Oral Anticoagulants (NOACs) in Non-Valvular Atrial Fibrillation 07/03/2013 1)Stroke/Embolism: absolute differences minimal when INR control with warfarin reasonable (TTR=>65%). 2)Stroke/Embolism: Dabi 150mg BID vs Warf; NNT=88/~2yr (no difference with 110mg BID dose, but less bleeding); open label RCT. 3)Stroke/Embolism: Riva 20mg daily vs Warf; non- inferiority trial design (ITT analysis favoured Riva but did not achieve superiority); double-blind RCT 4)Stroke/Embolism: Apix 5mg BID vs Warf; NNT=167/~2yrs; double-blind RCT. Also ␣␣ death NNT=132/~2yr 5)ICH: Dabi vs Warf; NNT=116/~2yr 6)ICH: Riva vs Warf; NNT=250/~2yr 7)ICH: Apix vs Warf; NNT=128/~2yr 8)GI Bleed: Dabi vs Warf; NNH=100/~2yr 9)GI Bleed: Riva vs Warf; NNH 100/~2yrs 10)GI Bleed: Apix vs Warf; no difference 11) Major Bleed: Dabi 150mg BID vs Warfarin; no difference; however 110mg BID had reduced major bleeding (NNT=77/~2yr) but also less benefit. 12)Major Bleed: Riva vs Warf; no difference 13)Major Bleed: Apix vs Warf; NNT=67/~2yr 14) Manage Bleeding: Warfarin - real world experience,& options include PCC & Vitamin K for reversal. New agents have less experience & lack antidote. However shorter half life of new agents means less time till anti- coagulation status returns to normal. Life-threatening/ fatal bleed was less in dabi / riva trials. However, ISMP Jan 2013 found that bleeds with Dabi 5x more fatal than bleeds with warfarin. Peri-procedural: less experience & thus more havoc in managing NOACs. 15) MI Risk: Dabi vs Warf; initial ␣␣ risk of borderline significance (p=0.048); reanalysis slightly different & non-significant(p=0.06bothdoses). Controversial; concerning to some. [Warf considered protective.] 16) Discontinuation rates vs Warf: lower with Apix (NNT=45/~2yrs); higher with Dabi (NNH=25/~2yr); also more dyspepsia with Dabi (NNH=18/2yr). 17) All new agents lack study & experience in patients with decreased renal fx. Dabi & Riva contraindicated (CI) if CrCl <30ml/min. Warfarin can be used. Since AFib patients often older, impaired renal fx an issue. 18) Economic review found new anticoagulants more costly than warfarin even after consideration for cost of INR monitoring was built in. However, “soft” indirect costs (e.g. time/travel to the patient) not included & may be assessed individually. Direct cost/month: Warf $35, Dabi $110, Riva $100, Apix 5 BID$140. 19) Half life of new agents is shorter. “Cons” of this are that Dabi & Apix require BID dosing; poor compliance (missed doses) will result in earlier loss of anticoagulation status; “Pros” are earlier achieve anticoagulation after starting & return to normal after holding if over-coagulated. 20) INR “Con” is the inconvenience factor; but “Pro” is ability to assess anticoagulation status stroke/bleed. 21) Warfarin has 60yrs “real world” experience; new agents have <1-2 yrs & in limited populations. This factor will change with use over the next 3-5+ yrs. 22) Valvular AFib: Warf OK, NOACs not indicated; Dabi CI

25 Anticoagulants (VTE, Afib, Valve disease)
Agent Cost Convenience Warfarin ~ $40/mo (with INR monitoring) QD po INR q3d – q1mo (ODB covered) Dabigatran $110/mo BID po (ODB w/ LU code 431 for AFib) Rivaroxaban $100/mo QD with food (ODB w/ LU code post-op TRK/THA) Apixaban $140/mo No coverage yet

26 Summary Antiplatelets Anticoagulants
Small differences in efficacy or toxicity, dictate that cost will drive selection. = ASA Combination therapy where indicated Anticoagulants Small differences in efficacy and important unknowns in newer agents (age effects, renal dysfunction, lack of antidotes) dictate selection of warfarin except for carefully selected patients with significant compliance barriers due to the inconvenience of INR testing.

27 Anti-depressants & Anxiolytics
Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2013

28 Anti-depressants & Anxiolytics
Selection of therapy: Efficacy: All equivalent! N.B. Wouldn’t use Bupropion for anxiety Therefore, tailor therapy based on potential toxicities! Meta-analyses that include grey literature trials show an over-estimation of efficacy and an under-appreciation of toxicity. SSRI’s: Fluoxetine, sertraline, (es)citalopram, fluvoxamine, paroxetine SNRI’s: (des)venlafaxine, duloxetine Mirtazapine Bupropion TCA’s: Amitriptyline, nortriptyline, despramine, imipramine, clomipramine, doxepin MAOi’s: (+++ types) Moclobemide (reversible) Phenelzine (irreversible) etc. etc.

29 Toxicities Anti-cholinergic effects
Paroxetine Mirtazipine (des)Venlafaxine TCAs: amitriptyline > nortriptyline > desipramine N.B. Anti-cholinergic, anti-histaminergic & weight gain effects often go hand-in-hand. Wt gain is usually minimal Some subpopulations gain++ Sedation TCAs Fluvoxamine Paroxetine (less extent) Mirtazapine Trazodone Activation Fluoxetine Bupropion (des)Venlafaxine Moclobemide Anticholinergic toxidrome - blurred vision, coma, decreased bowel sounds, delirium, dry skin, fever, flushing, hallucinations, ileus, memory loss, mydriasis (dilated pupils), myoclonus, psychosis, seizures, and urinary retention. Complications include hypertension, hyperthermia, and tachycardia. Anticholinergic toxidrome = “Blind as a bat, mad as a hatter, red as a beet, hot as a hare, dry as a bone, the bowel and bladder lose their tone, and the heart runs alone.”

30 Toxicities GI side effects QTc prolongation (TdP) Sexual dysfunction
Nausea - SSRIs Constipation - TCAs Diarrhea - sertraline, fluoxetine, paroxetine, duloxetine QTc prolongation (TdP) TCA’s Citalopram > 40mg/day Escitalopram > 20mg/day Sexual dysfunction SSRIs (>30% !) TCAs N.B. More serotonin = less libido More dopamine = more libido Drug/disease interactions Least with: (es)citalopram, mirtazapine, moclobemide, sertraline, (des)venlafaxine Moclobemide: no tyramine restrictions (unlike irrev MAOi’s!) PMID:

31 Anti-depressants & Anxiolytics
Cost All ~ $25 - $35 / month Newest agents, without generics cost more. Bupropion XL $45/mo Escitalopram $65/mo Paroxetine CR $60/mo Not covered under ODB Desvenlafaxine $85/mo Convenience Most once daily Bupropion SR – BID Bupropion XL – QD Moclobemide - BID

32 The Evils of Benzodiazepines (Yes, this includes “z-drug, non-benzo alternatives” Eg. Zopiclone)
Formerly one of the most commonly prescribed drug families of the 1960’s and 1970’s. In 1975 – 100 million Rxs written in USA alone Efficacy – excellent SHORT term efficacy Sedation & anxiolysis Rapid tolerance is developed Toxicity – addictive! D/C’ing after tolerance develops is VERY hard Long term risk of dementia, falls, and memory impairment Withdrawal can be fatal Cost & Convenience – Hey!, Fuggetabout-it!

33 Summary Highly variable response in efficacy Trial and error
All ~ equivalent in efficacy Trial and error Tailor to potential toxicities to maintain compliance Focus on relative toxicities! Efficacy often overestimated and toxicity often underestimated Avoid Benzodiazepines and Zopiclone (addictive) Even Rx’s for 10 tabs often snowball into chronic use.

34 Anti-psychotics Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Assistant Professor, Dept of Family Medicine, University of Ottawa Clinical Pharmacist, Bruyere Academic Family Health Team April 2013

35 Anti-psychotics Typical (1st gen / conventional) (Relative terms) Atypical (2nd gen)
Butyrophenones Haloperidol & Droperidol Phenothiazines Chlorpromazine & Fluphenazine Perphenazine & Prochlorperazine Thioridazine & Trifluoperazine Mesoridazine & Periciazine Promazine & Triflupromazine Levomepromazine & Promethazine Pimozide Thioxanthenes Chlorprothixene & Clopenthixol Flupenthixol & Thiothixene Zuclopenthixol Clozapine Olanzapine Quetiapine Risperidone Aripiprazole Ziprasidone Paliperidone Asenapine etc.

36 Anti-psychotics Efficacy
No clinically relevant differences (variable responses) ?Olanzapine superiority? See CATIE trial Exception: Clozapine – clearly superior As ever, when efficacy is ~ equivalent, choose therapy based on potential toxicities CATIE trial discussion: And:

37 Anti-psychotics Toxicities: Clozapine:
Agranulocytosis (10x higher risk vs other antipsychotics) Hence, mandatory CBC q2-4weeks Therefore, last line therapy, despite superior efficacy

38 Toxicities Sedation Tardive Dyskinesia Anticholinergic effects
Quetiapine Olanzapine Clozapine Typicals Least: haloperidol, risperidone, aripiprazole?, ziprasidone? Weight gain Tardive Dyskinesia Typicals Least: Clozapine (esp), all atypicals Anticholinergic effects Clozapine Least: risperidone, quetiapine, haloperidol Rxfiles.ca -

39 Toxicities EPS Hypotension QTc prolongation Typicals Clozapine
Least: atypicals QTc prolongation Clozapine Paliperidone Ziprasidone Pimozide Asenapine Thioridazine Least: Risperidone, haloperidol, aripiprazole, olanzapine, low dose quetiapine Hypotension Clozapine Risperidone Typicals Least: olanzapine, haloperidol, ziprasidone, paliperidone

40 Antipsychotics Cost Convenience ~ $20 - $40/month More expensive:
Newest agents: Aripiprazole Ziprasidone Paliperidone Asenapine Clozapine Quetiapine (XR) Olanzapine (Zydis) Convenience Most BID po Some injectable, long acting forms Risperidone Paliperidone Flupentixol Pipotiazine Fluphenazine Zuclopenthixol Haloperidol Olanzapine Zydis (melts) Risperidone M-tab (melts)

41 Summary Choose anti-psychotics based on potential toxicities
Learn two or three very well that complement each other. Low threshold to confer with psychiatry or pharmacy Rxfiles – excellent comparison charts to help guide therapy

42 Comments, Questions & Requests?
Monday & Fridays: ext 238 Tuesday, Wednesday, Thursday: ext 327 Halil, PharmD


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