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 evidence-based.

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 ImplicationsLong-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 long-term 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 eventsstatin 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 hypertensionTotal 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 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.

Clinical implicationsIf 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???