Clinical case

Pharmacotherapy optimisation

Mercredi 30.11.2016

Dr Bertrand Guignard

Process of Pharmaceutical care

1)Drug interaction

2)Subtherapeutic dosage

3)Overdosage

4)Drug use with no valid indication

5)Untreated indication

6)Improper drug selection

7)Adverse drug reaction

8)Failure to receive drug

Hepler CD, Strand LM (1990) Opportunities and responsibilities in pharmaceutical care. Am J Hosp Pharm 47 (3):533-543

Case • Mr. PN, 62 years old

• American patient in Holiday in Switzerland

• Admitted 31.03.15 for a suspicion of pneumonia with secondary decompensated heart failure.

• Productive cough with green-coloured expectorations for 5 days, an increasing shortness of breath for 3 days with wheezing, currently stage IV, and presence of worsening leg pitting edema.

• This patient is known for a “two-pillow” orthopnea, a paroxysmal nocturnal dyspnea, and a poor adherence to medication and dietary sodium restriction.

Case • Medical History:

– Ischemic and rhythmic heart disease with • Inferior-posterior NSTEMI secondary to an occlusion of the left marginal artery in

2010, treated by percutaneous coronary intervention plus placement of 2 bare-metal stents.

• Persistent atrial fibrillation.

• Severe left systolic dysfunction (LVEF 20%) on transthoracic echocardiography of 21.08.14.

– Cardiovascular risk factors • Hypercholesterolemia et hypertriglyceridemia

• Hypertension

• Obesity

• Tobacco use

– Chronic obstructive pulmonary disease (COPD) • Group B with FEV1 at 65% predicted (spirometry of October 2014)

– Suspicion of sleep apnea

Case • Medical problems:

– COPD exacerbation or pneumonia

– Secondary decompensated heart failure

• Labs: Normes 31.03.15 02.04.15

Sodium 136-144 mmol/L 138 mmol/L 137 mmol/L

Potassium 3.6-4.6 mmol/L 4.0 mmol/L 4.2 mmol/L

Creatinine

(estimated GFR)

< 106 μmol/L 75 μmol/lL

(102 mL/min/1.73m2)

85 μmol/lL

(92 mL/min/1.73m2)

Total cholesterol < 6.5 mmol/L 5.2 mmol/L

LDL-cholesterol < 4.0 mmol/L 2.9 mmol/L

Triglycerides < 2.0 mmol/L 3.1 mmol/L

BNP < 100 ng/L 350 ng/L 280 ng/L

INR 2.2 3.7

• Patient observations

31.03.15 02.04.15

BP 137/67 160/80

Pulse 100 bpm 95 bpm

O2 sat room air 94% 93%

Medication MEDICATION AT HOME (Medication history of 31.03.2015)

Coumadin cpr Warfarine Selon INR PO

Aspirine cpr remplacé par Acetylsalicylic acid 81 mg 1-0-0 PO

Aspirine Cardio cpr Acetylsalicylic acid 100 mg 1-0-0 PO

Concor cpr Bisoprolol 7.5 mg 1-0-0 PO

Digoxine cpr Digoxin 0.25 mg 1-0-0 PO

Tylenol cpr eff remplacé par Acetaminophen 650 mg 1-1-1-1 PO

Dafalgan cpr eff Paracetamol 1000 mg 1-1-1-1 PO

Aldactone cpr Spironolactone 25 mg 1-0-0 PO

Torem cpr remplacé par Torsemide 20 mg 1-0-1 PO

Lasix inject Furosemide 120 mg/24h continu IV

Nexium cpr Esomeprazole 40 mg 1-0-1 PO

Cipralex cpr Escitalopram 10 mg 1-0-0 PO

Seretide Diskus Salmeterol + fluticasone 50/250 mcg 1-0-1 inh

Spiriva caps inhal Tiotropium 18 mcg 1-0-0 inh

Seresta cpr Oxazepam 15 mg 1-0-1 PO

Lipanthyl M caps Micronized fenofibrate 200 mg 1-0-0 PO

Ezetrol cpr Ezetimibe 10 mg 1-0-0 PO

Augmentin Amoxicillin + clavulanate 1.2 g q6h IV

Klacid Clarithromycin 500 mg Q12h PO

Dospir Salbutamol-ipratropium 1 dose 1-1-1-1 inh

MEDICATION ADDED DURING HOSPITALIZATION

QUESTION 1 Mr. PN currently receives clarithromycin before ruling out pneumonia to atypical pathogens. Which drugs could interact with clarithromycin?

1. Esomeprazole

2. Bisoprolol

3. Digoxin

4. Escitalopram

5. Warfarine

6. Salmeterol

7. Fluticasone

8. Fenofibrate

1. 2. 3. 4. 5. 6. 7. 8.

0% 0% 0% 0%0%0%0%0%

Comment

1. Esomeprazole No interaction with clarithromycin reported in the literature. Esomeprazole is a substrate of CYP 3A4 (minor pathway), but it is especially a substrate of CYP 2C19 (major pathway).

7. Fenofibrate No interaction with clarithromycin reported in the literature. Inactivation by glucuronidation and renal excretion.

Comment 3. Bisoprolol

Bisoprolol is a substrate of CYP 3A4 (minor pathway), but is especially a substrate by P-gp (major pathway). A theoretical interaction is possible.

However, no interaction with clarithromycin, nor with other P-gp inhibitors, was reported in the literature.

It seems prudent to monitor BP and pulse during the treatment with clarithromycin.

Commentaire 3. Digoxin

Correct. Digoxin is a substrate of P-gp and clarithromycin is a P-gp inhibitor.

If clarithromycin is maintained, digoxinemia should be monitored after 3-5 half-lives (min 4 days)

Gomes T, Mamdani MM, Juurlink DN, et al: Macrolide-induced digoxin toxicity: a population-based study . Clin Pharmacol Ther 2009; 86(4):383-386.

Comment 4. Escitalopram

Correct. Clarithromycin and escitalopram may induce a QTc prolongation (PD interaction).

Moreover, escitalopram is a substrate of CYP 3A4 (minor pathway) and of P-gp, which are inhibited by clarithromycin. However, escitalopram is also a substrate of CYP 2C19 (major) and 2D6 (minor) which may compensate (therefore, a PK interaction is less likely).

Doth drugs can be administered together (escitalopram max 20 mg/j), but QTc interval should be monitored and treatment shoud be modified if QTc > 470 ms in women and > 450 ms in men or if QTc prolongation ≥ 60 msec.

https://www.crediblemeds.org

Prolong QTc interval AND clearly associated with a known risk of TdP

Can cause QTc prolongation BUT currently lack evidence for a risk of TdP

Prolong QTc interval AND risk of TdP BUT only if overdosage or PK ou interaction

All theses cathegories, and drugs that can prolong QTc only in case of congenital long QT syndrome

QT prolongation: which drugs?

https://www.crediblemeds.org

QT prolongation: consequences

Torsade de pointes

Ventricular fibrillation

Sudden death

QT prolongation Drugs

Genetics

Risk factors

Early after-depolarizations

QT prolongation: monitoring

Current Medical Research & Opinion Vol. 29, No. 12, 2013, 1719–1726

400 ms 520 ms

Correction with the Bazett formula QTc = QT corrected for a pulse of 60/min RR

QTQTc

Definition of QT prolongation: ♀ > 470 ms et ♂ > 450 ms

rateheart

60RR

Comment

4. Warfarine

Correct. As acenocoumarol, warfarine is a substrate of CYP 2C9 (major), 2C19 (minor) and 1A2 (minor), but moreover of CYP 3A4. In a case-control study, 1.86-fold more hospitalisations for bleeding with macrolides.

Baillargeon J, Holmes HM, Lin YL, et al: Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med 2012; 125(2):183-189.

Comment 5. Salmétérol

Correct. Salmeterol is a substrate of CYP 3A4, which is inhibited by clarithromycin. Salmeterol AUC increased by a 16-fold factor with ketoconazole (another CYP 3A4 inhibitor). The systemic effect may be increased. As the treatment with clarithromycin is short, a treatment modification is not necessary. Only BP and pulse monitoring, and be aware of possible agitation symptoms.

6. Fluticasone

Correct. Fluticasone is a substrate of CYP 3A4, which is inhibited by clarithromycin. Oral bioavailability of fluticasone is <1% (first pass effect). This bioavailability may increase up to 350-fold in case of CYP 3A4 inhibition. The systemic effect may be increased. As the treatment with clarithromycin is short, a treatment modification is not necessary.

Valin N, De Castro N, Garrait V, Bergeron A, Bouche C, et al. (2009) Iatrogenic Cushing’s syndrome in HIV-infected patients receiving ritonavir and inhaled fluticasone: description of 4 new cases and review of the literature. J Int Assoc Physicians AIDS Care (Chic) 8: 113-121.

QUESTION 2 Mr. PN improves his edema with IV furosemide. He can be switched again on oral torsemide. How to manage the heart failure on the long term and reduce the incidence of new exacerbations?

1. Increase torsemide at 40 mg BID.

2. Add lisinopril 2.5 mg die PO (in the absence of contraindication) and increase the dose every 2-4 weeks according to BP.

3. Stop digoxin et increase the dose of bisoprolol every 2-4 weeks according to BP and pulse.

4. Stop digoxin, add lisinopril 2.5 mg die PO (in the absence of contraindication), continue bisoprolol and increase the dose of both drugs every 2-4 weeks according to BP and pulse.

1. 2. 3. 4.

0% 0%0%0%

Comment • Answer 2: Add lisinopril, maintain BB and digoxin.

• Answer 4: Add lisinopril, maintain BB and stop digoxine.

Beta-blockers and ACE-I/ARB are the cornerstone of the treatment of systolic heart failure (LVEF ≤ 40%), because they decrease morbidity et la mortality. A mineralocorticoid receptor antagonist may be introduced only if beta-blockers and ACE-I/ARB are at target dose (or max dose tolerated by the patient). Digoxin only decreases morbidity (rate of hospitalisation) and may be added only after an ACE-I/ARB, a BB, an MRA, and sacubitril/valsartan or ivabradine or in case of contraindication.

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal (1016) Jul 14;37(27):2129-200.

Comment • Answer 1: Increase torsemide dosage.

• Answer 3: Maintain BB and stop digoxin, no ACE-I/ARB.

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal (1016) Jul 14;37(27):2129-200.

QUESTION 3 Mr. PN receives an antiplatelet agent (Aspirin) and an anticoagulation (VKA). Is it necessary?

1. No. Aspirin is sufficient to cover the ischemic heart disease and the atrial fibrillation.

2. No. Aspirin is sufficient, but the dose should be increased at 300 mg die.

3. Yes. An antiplatelet agent is warranted to cover the ischemic heart disease and a VKA (INR 2-3) is warranted to cover the atrial fibrillation.

4. No. This is a stable ischemic heart disease. If the patient receives an anticoagulant, Aspirin might be stopped. 1. 2. 3. 4.

25% 25%25%25%

Comment • Answer 1: Aspirin is sufficient to cover the ischemic heart

disease and the atrial fibrillation.

• Answer 2: Aspirin is sufficient, but the dose should be increased at 300 mg die.

The CHA2DS2-VASc score of Mr. PN is 3

ESC Guidelines for the management of atrial fibrillation. European Heart Journal (2010) 31, 2369–2429

Comment • Answer 4: This is a stable ischemic heart disease.

If the patient receives an anticoagulant, Aspirin might be stopped.

Lip GYH et al. European Heart Journal (2014) 35, 3155–3179

QUESTION 4 Is the management of hypercholesterolemia optimal?

1. Yes. Total cholesterol at 5.2 mmol/L and LDL at 2,9 mmol/L are normal values.

2. No. Fenofibrate could be up-titrated.

3. No. Fenofibrate and ezetimibe should be replaced by atorvastatin 40 mg.

4. No. Fenofibrate should be replaced by atorvastatine 20 mg et ezetimibe may be maintained.

1. 2. 3. 4.

0% 0%0%0%

ATP III

ATP IV: no more target-values!

National Institutes of Health National Heart Lung and Blood Institute. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. Grundy SM, Cleeman JI, Bairey Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–39.

Stone NJ, Robinson J, Lichtenstein AH, Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K,WilsonPW. 2013 ACC/AHAGuideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013 [Epub ahead of print].

2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. European Heart Journal (2016) 37, 2999–3058.

• Answer 1: Total cholesterol at 5.2 mmol/L and LDL at 2,9 mmol/L are normal values.

Comment

• Answer 2: Fenofibrate could be up-titrated.

Max dosage 200 mg die already reached

• Answer 4: Fenofibrate may be replaced by atorvastatine 20 mg et ezetimibe may be maintained.

Commentaire

2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. European Heart Journal (2016) 37, 2999–3058.

Koda-Kimble & Young’s Applied Therapeutics: The Clinical Use of Drugs, 10ème édition, 2012, Lippincott Williams and Wilkins

• Answer 3: Fenofibrate and ezetimibe may be replaced by atorvastatin 40 mg.

Commentaire

QUESTION 5 Which drug could pose be problematic with the heart failure?

1. Escitalopram

2. Paracetamol

3. Bisoprolol

4. Aspirin

1. 2. 3. 4.

25% 25%25%25%

Commentaire • Answer 2: Paracetamol

Adapté de Gransard C et al. Médicaments à haute teneur en sodium: apport en sel méconnu et sous-estimé. Poster SFPC Bordeaux, 2006.

Comment

1. Escitalopram No contraindication.

3. Bisoprolol Treatment of choice in systolic heart failure, but a too fast up-titration could worsen a heart failure.

4. Aspirin No contraindication. Frequently prescribed in heart failure (secondary to an ACS).

QUESTION 6 For a group B COPD, is the present treatment appropriate?

1. Yes. Patients of group B should at least benefit from an inhaled corticosteroid. Long-acting beta-agonists are optional.

2. Yes. Patients of group B should benefit from a long-acting beta-agonist, a long-acting anticholinergic, and an inhaled corticosteroid.

3. No. Patients of group B do not require an inhaled corticosteroid.

4. No. Patients of group B do not require a long-acting anticholinergic.

1. 2. 3. 4.

0% 0%0%0%

Comment • Answer 3: Patients of group B do not require an inhaled

corticosteroid.

GOLD. Global Strategy for Diagnosis, Management, and Prevention of COPD. Update 2015

QUESTION 7 After all these treatment modifications, which drug would have no more valid indication and could be stopped?

1. Bisoprolol

2. Esomeprazole

3. Spironolactone

4. Escitalopram

1. 2. 3. 4.

0% 0%0%0%

CAPP-Info n° 51 Indications de l’esoméprazole aux HUG http://pharmacoclin.hug-ge.ch/_library/pdf/cappinfo51.pdf

Comment Answer 2: Esomeprazole