Transcript Less than helpful therapies

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.
 Coordinating Editor, Cochrane Hypertension Group.
 No competing interests with Drug or other Industries.
"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.
Less than helpful
therapies
Euphemism for:
Therapies where the harms outweigh or are equal to the
benefits
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.
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 evidencebased.
What are meaningful outcomes?
 Total (all cause) mortality
 Total morbidity and mortality (total serious adverse
events)
 Absolute benefits and absolute harms are known.
Proven harmful therapies
 Dual antiplatelet therapy.
 Antipsychotics for delirium and agitation in the elderly.
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]
Clinical Implications
Long-term dual antiplatelet therapy is contraindicated.
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.
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?
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.
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?
Proton pump inhibitors (PPIs)
 Omeprazole
 Esomeprazole
 Lansoprazole
 Dexlansoprazole
 Pantoprazole
 Rabeprazole
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
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
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
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 longterm therapy outweigh the harms.
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.
Total serious adverse events
statin vs placebo - primary
prevention
Total serious adverse events
statin vs placebo CHF
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.
Antihypertensive drugs vs placebo in
mild hypertension
Total cardiovascular events
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.
A Systematic Review
of the Efficacy of
Bisphosphonates
Therapeutics Letter
Sept-Oct, 2011
Conclusions
There are no proven clinically meaningful benefits for
bisphosphonates in postmenopausal women without a prior
fracture or vertebral compression.
Clinical implications
If there is no net health benefit, prescribing is an unnecessary
inconvenience to patients and a waste of health care
resources.
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.
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 .
Questions???