less than helpful therapies
DESCRIPTION
Less than helpful therapies. James (Jim) M Wright, MD, PhD, CRCP(C) Professor Anesthesiology, Pharmacology & Therapeutics and Medicine University of BC. Declaration. Co-Managing Director, Therapeutics Initiative. Editor-in-Chief, Therapeutics Letter. - PowerPoint PPT PresentationTRANSCRIPT
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Less than helpful therapies
James (Jim) M Wright, MD, PhD, CRCP(C)
Professor
Anesthesiology, Pharmacology & Therapeutics and Medicine
University of BC
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Declaration
Co-Managing Director, Therapeutics Initiative.
Editor-in-Chief, Therapeutics Letter.
Coordinating Editor, Cochrane Hypertension Group.
No competing interests with Drug or other Industries.
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"Less than Helpful Therapies”
Learning Objectives
To appreciate that many common long-term drug therapies are not supported by gold standard evidence.
To become aware of long-term drug therapies that have been proven to cause more harm than benefit.
To learn some long-term drug therapies that are likely to cause more harm than benefit.
To find out the solution to this prevalent clinical dilemma.
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Less than helpful therapies
Euphemism for:
Therapies where the harms outweigh or are equal to the benefits
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Outline
How do we know that a therapy is more harmful than beneficial?
Therapies proven to be more harmful than beneficial.
Therapies likely to be more harmful than beneficial.
Therapies where harms equal the benefits.
Conclusions and solutions.
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What does proven mean?
Based on randomised controlled trial(s) (RCTs) measuring meaningful outcomes.
Evidence-based therapy – based on RCTs proving benefits outweigh harms (Gold standard evidence).
Many common long-term therapies are not evidence-based.
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What are meaningful outcomes?
Total (all cause) mortality
Total morbidity and mortality (total serious adverse events)
Absolute benefits and absolute harms are known.
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Proven harmful therapies
Dual antiplatelet therapy.
Antipsychotics for delirium and agitation in the elderly.
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Dual antiplatelet therapy
Secondary prevention of small sub-cortical strokes (SPS3) RCT (NEJM 2012;367;817-825).
ASA plus clopidogrel vs ASA plus placebo.
3020 patients, mean age 63, 63% men, 3.4 year follow-up.
Total mortality, HR = 1.52 [1.14–2.04], ARI = 2.3%.
Major hemorrhage, HR = 1.97 [1.41—2. 71], ARI = 3.2%.
Disabling or fatal stroke, HR = 1.06 [0.69–1.64]
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Clinical ImplicationsLong-term dual antiplatelet therapy is contraindicated.
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Antipsychotics (neuroleptics) in the elderly
Elderly patients with dementia and behavioral disturbances.
Systematic review of antipsychotic vs placebo (2005).
17 RCTs in 5106 patients for 10 weeks.
Mortality: antipsychotic 4.5%, placebo 2.6%
ARI = 1.9%, NNH = 53 for 10 weeks.
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What happened? FDA created a black box
warning for these drugs as a class.
Prescribing of antipsychotics in this setting has increased despite the knowledge that
it is harmful. Why?
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Therapies where the harms likely outweigh the benefits
Long-term non-steroidal anti-inflammatory drug (NSAID) therapy.
Long-term proton pump inhibitor (PPI) therapy.
Long-term sedative hypnotic therapy.
Long-term antidepressant therapy.
Long-term RCTs versus placebo are lacking.
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NSAIDs (selective and non-selective COX-2 inhibitors)
Associated or proven harms
Upper GI ulcers and hemorrhage
Fluid retention and increase in blood pressure
Increased myocardial infarction and stroke
Accelerated joint destruction
Delayed or non-union of fractures
It is likely that these harms outweigh the benefits?
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Proton pump inhibitors (PPIs)Omeprazole
Esomeprazole
Lansoprazole
Dexlansoprazole
Pantoprazole
Rabeprazole
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Long-term PPIs: Associated or proven harms
Withdrawal rebound hyperacidity with symptoms
Increased incidence of fractures
Increased incidence of community acquired pneumonia
Magnesium deficiency
Vitamin B12 deficiency
It is likely that these harms outweigh the benefits
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Long-term sedative hypnotic therapy(benzodiazepines, Z-drugs)
Associated or proven harms
Tolerance and loss of efficacy
Withdrawal insomnia and anxiety
Memory loss and cognitive decline
Falls and fractures
Motor vehicle accidents
It is likely that these harms outweigh the benefits
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Long-term antidepressants(newer and older drugs)
Short-term benefits small and questionable
Associated or proven harms
Sexual dysfunction
Suicidality, suicide and violence
Mania and diagnosis of bi-polar disorder
Motor vehicle accidents
It is likely that these harms outweigh the benefits
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What is needed?
Recognition that the harms likely outweigh the benefits in these settings.
Limiting prescribing to durations that have been studied in RCTs.
Explaining the situation to patients and tapering and stopping these drugs in many.
Long-term RCTs to test whether the benefits of long-term therapy outweigh the harms.
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Therapies where the harms likely equal the benefits.
Statins for primary prevention.
Statins for congestive heart failure.
Antihypertensives for mild hypertension.
ASA for primary prevention.
Bisphosphonates for primary prevention.
Long-term RCTs have been conducted.
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Total serious adverse events statin vs placebo - primary prevention
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Total serious adverse eventsstatin vs placebo CHF
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Cochrane Library
Diao D, Wright JM, Cundiff DK, Gueyffier F
Pharmacotherapy for mild hypertension
Cochrane Database of Systematic Reviews
2012, Issue 8. Art. No.: CD006742. DOI: 10.1002/14651858.CD006742.pub2
Four trials (8912 male and female subjects) studied for 4 to 5 years.
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Antihypertensive drugs vs placebo in mild hypertensionTotal cardiovascular events
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Antiplatelet Chemoprevention of Occlusive Vascular Events
and Death
Therapeutics Letter Issue 37; Sep - Oct 2000
PRIMARY PREVENTION
Benefit of antiplatelet therapy has not been shown to exceed harm in patients without proven
vascular occlusive disease.
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A Systematic Reviewof the Efficacy ofBisphosphonates
Therapeutics LetterSept-Oct, 2011
Conclusions
There are no proven clinically meaningful benefits for bisphosphonates in postmenopausal women
without a prior fracture or vertebral compression.
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Clinical implicationsIf there is no net health benefit, prescribing is an
unnecessary inconvenience to patients and a waste of health care resources.
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Conclusions
Examples presented are just the tip of the iceberg.
As Internists we must know when our prescriptions are:
Proven to be more harmful than beneficial.
Unproven but likely to be more harmful than beneficial.
Likely to cause as much harm as benefit.
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Solutions
Limit prescribing to settings where the therapy is proven to be more beneficial than harmful as much as possible.
Insist on independent funding for RCTs testing long-term therapy.
Participate in RCTs for long-term therapy .
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Questions???