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Prescribing a Drugectomy –
Who, Why, What, When,
Where, and How

Any patient that has ongoing
“side-effects/cost”

James M...
Medication Use

Issues to Consider
~ 25-50% of people diagnosed with HTN don’t have
elevated blood pressure - BMJ 2002;325...
TREATMENT !
TARGETS

18 “NEGATIVE” STUDIES IN A ROW
LIPIDS!
AIM-HIGH, HPS2-THRIVE (niacin)!
ACCORD (fibrates)!
dalOUTCOMES ...
Quality of life comparisons
QOL
utilities

Mild stroke
Angina
Diabetic neuropathy

0.7
0.64
0.66

Comprehensive diabetes c...
“ACUTE” Heartburn
HEALING SYMPTOM/RESOLUTION

Patients who respond in the PPI group!

How to tell if a drug
worked/is work...
Rationale for starting with
“very” low doses

Limitations of using “very”
low doses

1)!There is rarely a need to get an i...
What you should shoot for
Start with really low doses!
No hurry!

883 heart failure patients - age - 73!

Surrogate marker...
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Prescribing a Drugectomy – Who, Why, What, When, Where, and How

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Presented at Optimizing Medications workshop in Vancouver by James McCormack

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Transcript of "Prescribing a Drugectomy – Who, Why, What, When, Where, and How"

  1. 1. Prescribing a Drugectomy – Who, Why, What, When, Where, and How Any patient that has ongoing “side-effects/cost” James McCormack ! B.Sc. (Pharm), Pharm.D.! Professor! Faculty of Pharmaceutical Sciences! University of British Columbia! Vancouver, BC! therapeuticseducation.org! mystudies.org! @medmyths Any patient that has had a drug added WITHOUT being given an informed choice ! Any drug that was not started at the VERY lowest dose Understanding of the ballpark numbers - benefits and harms! No hurry! Do the experiment! DON’T start with low doses! Re-evaluate! Start with VERY low doses Most standard doses are excessive! No guilt Doxepin (Sinequan) Depression - start 25-50 mg - optimal 75mg -150mg up to 300mg! J Clin Psychiatry 2001;62:453-63 “The results support the effectiveness of low doses (25-50 mg) of doxepin to improve sleep” Sleep 2007; 30: 1555–61 Efficacy and Safety of Three Different Doses of Doxepin in Adults with Primary All three doses worked better than placebo! AND
 NO side effects over placebo A recommended low dose was still 25-50 times TOO HIGH Any patient/drug you haven’t re-eVALUated annually “starting drugs is like the bliss of marriage, stopping them is like the agony of divorce”! Need! Dose! Duration! Guiltless choice
  2. 2. Medication Use Issues to Consider ~ 25-50% of people diagnosed with HTN don’t have elevated blood pressure - BMJ 2002;325:815–7! Canada - 2008 data! Patients over the age of 65! 5 or more drug classes - 62%! 10 or more - 21%! 15 or more - 6%! BC - 2010 data! 10-25% use 5 or more Rx drugs! Issues to Consider Symptoms - many clinical trials show a placebo group response of 20-30%! Disease states fluctuate! Prevention - patients believe “prevention” drugs produce a 70% absolute benefit over 5 years Clin Med 2002;2:527-33 when at most only ~ 20% could benefit over a lifetime! The frequency and dose used for many drugs is often way too much Guides to safe prescribing Beers, the most popular: weak evidence1! Assoc with hospitalization in community elderly! No other consistent associations! Drug Burden Index (DBI) ! DBI assoc decreased physical function & falls2! Beers not3! STOPP5 may be better! STOPP slightly better to predict ADE & hospitalization 1) Ann Pharmacother 2007;41:438-48. 2) Am J Med (2009) 122, 1142-1149. J Am Geriatr Soc. 2011 May; 59(5):875-80. 3) J Clin Pharmacol published online 2 February 2011 2) Ann Pharmacother 2010;44:1725-32. 5) Age & Ageing 2008; 37: 673–79 Arch Intern Med. 2011;171:1013-1019. ~ 1/3 of patients diagnosed with asthma don’t have asthma - CMAJ 2008;179:1121-31! ~ 90% of COPD patients don’t get a clinically important benefit from their inhalers - N Engl J Med 2008;359:1543-54! ~ 85% of depressed patients don’t get a benefit from their antidepressant - Cochrane Library CD007954! ~ 50% of type 2 diabetics have an A1c level that if treated has been shown to NOT provide benefit and maybe even cause harm - Diabetes Care 2008;1:81-6, ACCORD, ADVANCE,VADT When you do a! Patient Medication History! HOW TO START THINKING CRITICALLY UNTIL PROVEN OTHERWISE! ! The drug and the dose are wrong!!!!!! Are these associations helpful? Hospitalization for Drug-related Adverse Events ! In people ≥65 ! Half happened in ≥80! 66% were unintentional overdoses ! 67% were: ! warfarin (33%), insulins (14%), oral antiplatelet agents (13%), and oral hypoglycemic agents (11%)! Prescribing rules (HEDIS, BEERS) would identify only 1-6% of the problems N Engl J Med 2011;365:2002-12
  3. 3. TREATMENT ! TARGETS 18 “NEGATIVE” STUDIES IN A ROW LIPIDS! AIM-HIGH, HPS2-THRIVE (niacin)! ACCORD (fibrates)! dalOUTCOMES (dalcetrapib)! Level A = recommendation based on evidence from ! BLOOD PRESSURE! ALTITUDE (aliskiren)! VALISH, AASK, ACCORD ! (aggressive BP lowering)! <2 mmo/L/80mg/dL DIABETES! multiple randomized trials or meta-analyses ACCORD, ADVANCE, VADT ! (aggressive A1c lowering)! ROADMAP (olmesartan)! ORIGIN (insulin)! SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin)! GENERAL! “The Expert Panel was UNABLE TO FIND RCT EVIDENCE to support titrating cholesterol-lowering ACTIVE (irbesartan/afib)! CRESCENDO (rimonabant)! VISTA-16 (Varespladib) drug therapy to achieve target LDL–C or non-HDL-C levels, as recommended by ATP III”! Typically “evidence-based” guideline recommendations! are not based on “solid” evidence 
 “Antihypertensive drugs used in the treatment of adults (primary prevention) with mild hypertension (systolic BP 140-159 mmHg and/or diastolic BP 90-99 mmHg) have not been shown to reduce mortality or morbidity in RCTs”! “Treatment caused 9% of patients to discontinue treatment due to adverse effects.” 11% Evidence Level (1 or A)! based on RCTs 14% 48% Evidence Level (3 or C)! based on opinion 55% August 2012 Canadian chronic disease state guidelines! blood pressure, cholesterol, glucose, and bone density 197 PAGES - 90,000 Words! 99 words (0.1%) - relevant to the issues of patients’ values and preferences “clinicians spend time exploring ways of reducing the level of the surrogate, even when the only options are interventions that do not improve, or may even worsen, a patient’s outlook”
  4. 4. Quality of life comparisons QOL utilities Mild stroke Angina Diabetic neuropathy 0.7 0.64 0.66 Comprehensive diabetes care 0.64 Ann Int Med 2011;155:340-1 Diabetes Care 2007;30:2478-83 2012 A1C of 8 - 14 “the desires and values of the patient should also be considered, since the achievement of any degree of glucose control requires active participation and commitment”! HYPOGLYCEMIA “Importantly, utilizing the percentage of diabetic patients who are achieving an HbA1c ,7.0% as a quality indicator, as promulgated by various health care organizations, is inconsistent with the emphasis on individualization of treatment goals”! ! Diabetes Care 2012;35:1364-79 PRIMARY PREVENTION! Helps you make an estimate of CVD risks for any patient! and then figure out benefits and harms for any CVD drug/ non-drug treatment FREE cvdcalculator.com How to tell if a drug worked/is working? Drugs for Symptoms! Acute self-limiting symptoms! You really can’t! “Chronic” symptoms - Maybe - with reassessment - Drugectomy or dose reduction! Need to have a rough idea of the response in the placebo group
  5. 5. “ACUTE” Heartburn HEALING SYMPTOM/RESOLUTION Patients who respond in the PPI group! How to tell if a drug worked/is working? ≈ 65% at 4 weeks, 85% at 8 weeks - DOUBLE DOSE ANOTHER 5%? ! Patients who respond to H2RA! Drugs for Prevention! ≈ 40% at 4 weeks, 55% at 8 weeks ! HTN, statins, diabetes, osteoporosis! Patients who respond in the placebo group ! ≈ 15% at 4 weeks, 30% at 8 weeks 8-9/10 patients will respond to a PPI! 3 of these improved not because of a drug! an additional 2-3 of these would have improved with an H2RA YOU really CAN’T! And likely over a lifetime a patient won’t benefit ... Cochrane Library CD003244 Prevention drugs QRISK Lifetime risk of CVD 50 year-old male - non smoker ! CHOL/HDL 4/SBP120 vs 7/180 Risk reduction meds ASA, statins - you can just stop them! Fibrates - please just stop them! 10% abs diff Blood pressure and diabetes drugs?! 20% abs diff 20 years ≈ 90% no benefit?! 45 years ≈ 80% no benefit? dosage should be reduced by 50%, with reassessment of blood pressure at 2 weeks! if the patient is still normotensive, reduce the dosage by another 50% (i.e., to 25% of the initial dose) and recheck the blood pressure in another 2 weeks http://www.qrisk.org/lifetime/index.php Symptom meds PPIs, NSAIDs etc Typically one should reduce the dose slowly - cut the dose in half or do something similar - change interval! Advantages of starting with “very” low doses ! 1)!Get the potential “placebo group effect” ! The dose likely wasn’t right in the first place! 2)!Patients are engaged in the process of finding the best dose for them! Put the onus on, and give the power to the patient to find the right dose 3)!Cost savings can be considerable and reduced adverse events! 4)!Most clinically relevant drug interactions can be avoided
  6. 6. Rationale for starting with “very” low doses Limitations of using “very” low doses 1)!There is rarely a need to get an immediate response! 2)!For many marketed drugs the recommended starting doses are too high ! 3) Cannot reliably predict pharmacodynamic variability - typically exceeds pharmacokinetic variability ! 4)!Approximately ¾ of side effects of drugs are dose related! 1) Does not apply to life threatening conditions! 2) Problem if you can’t easily identify a clinical endpoint - in frequents seizures! 3) Target doses - ACEI etc - HOWEVER!! 5) In animal research there is a wide dose-response relation humans are genetic mongrels Target DOSES ACE inhibitors, betablockers, ARBs - CHF! Class 1 recommendation “with a special focus on adherence, persistence, and up titration to recommended doses of ACE inhibitor/ARB and beta-blocker medication” All the TARGET dose evidence Drug ”achieving target doses should continue to be an important for practitioners” Absolute Benefits! Absolute! Harms Enalapril 4x 7-15x 0.5 None 8% 4 4/6% 3/7% 4x 0.5 None 10% Carvedilol goal Duration! (years) Carvedilol “every effort should be made to place virtually all patients on ACEIs and achieve the target dose for that ACEI”! High/low dose 8x 4 None 20% Losartan 3x 5 3% 3/7% Lisinopril Benefits - primarily hospitalizations! Harms - hypotension, withdrawal, dose reduction
  7. 7. What you should shoot for Start with really low doses! No hurry! 883 heart failure patients - age - 73! Surrogate markers! 66% class II, 29% class III! Randomised to bisoprolol (10 mg daily) or carvedilol (25 mg BID) and slowly up-titrated patients to the “RECOMMENDED” doses Fraction of dose Patients on dose at end 0 1/8 1/4 1/2 FULL 10% 10% 25% 25% 30% Eur J Heart Fail 2011;13:670-80 Is the benefit because of the effect on the surrogate?! Don’t measure obsessively! The most benefit is getting them from really not getting to really low! Target Doses! If you can get them to the doses in the studies GREAT but don’t sweat it nor let your patients sweat it! REMEMBER! Doubling the dose from 20-40mg or 40-80 mg changes cholesterol by ~5% % reduction in LDL cholesterol 60 10mg 20mg 40mg 80mg 45 30 15 Atorvastatin Simvastatin 10 mg - 70% of the effect! 20 mg - 85% of the effect! 40 mg - 90% of the effect Pravastatin Atorvastatin % LDL reduction 10 mg 20 mg 40 mg 80 mg 37 43 48 53 CD008226 Practical issues/ suggestions for cutting doses 1) Start with half of the lowest marketed dose for older established products! 2) For newly marketed medications start with a half or even a quarter of the lowest available dose! 3) Need a discussion with the patient! 4) Dosage forms - pill cutters, capsules, liquid! 5) Increase interval if can’t decrease dose Ann Intern Med 2008;148:656-61 Within-person coefficient of variation is ~7%! Single measurement - 95% CI! Total chol ~ - 0.80 to 0.80 mmol/L! LDL chol ~ - 0.5 to 0.5 mmol/L 0 Rosuvastatin HIGH, Average increase! in cholesterol! is 0.5-1%/year “After initial change only measure every 3-5 years” Guidelines and the Law “As per the Canadian Medical Association Handbook on Clinical Practice Guidelines, guidelines should NOT be used as a legal resource in malpractice cases as “their more general nature renders them insensitive to the particular circumstances of the individual cases.”

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