Less than helpful therapies

1. Less than helpful therapies James (Jim) M Wright, MD, PhD, CRCP(C) Professor Anesthesiology, Pharmacology & Therapeutics and Medicine University of BC

2. Declaration • Co-Managing Director, Therapeutics Initiative. • Editor-in-Chief, Therapeutics Letter. • Coordinating Editor, Cochrane Hypertension Group. • No competing interests with Drug or other Industries.

3. "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.

4. Less than helpful therapies Euphemism for: Therapies where the harms outweigh or are equal to the benefits

5. 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.

6. 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.

7. What are meaningful outcomes? • Total (all cause) mortality • Total morbidity and mortality (total serious adverse events) • Absolute benefits and absolute harms are known.

8. Proven harmful therapies • Dual antiplatelet therapy. • Antipsychotics for delirium and agitation in the elderly.

9. Dual antiplatelet therapy • Secondary prevention of small sub-cortical strokes (SPS3) RCT (NEJM 2012;367;817-825). • ASA plus clopidogrelvs 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]

10. Clinical Implications Long-term dual antiplatelet therapy is contraindicated.

11. 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.

12. 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?

13. 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.

14. 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?

15. Proton pump inhibitors (PPIs) • Omeprazole • Esomeprazole • Lansoprazole • Dexlansoprazole • Pantoprazole • Rabeprazole

16. 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

17. 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

18. 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

19. 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.

20. 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.

21. Total serious adverse events statinvsplacebo - primary prevention

22. Total serious adverse eventsstatinvs placebo CHF

23. 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.

24. Antihypertensive drugs vs placebo in mild hypertensionTotal cardiovascular events

25. Antiplatelet Chemoprevention of Occlusive Vascular Events and DeathTherapeutics 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.

26. A Systematic Reviewof the Efficacy ofBisphosphonatesTherapeutics LetterSept-Oct, 2011 Conclusions There are no proven clinically meaningful benefits for bisphosphonates in postmenopausal women without a prior fracture or vertebral compression.

27. Clinical implications If there is no net health benefit, prescribing is an unnecessary inconvenience to patients and a waste of health care resources.

29. Conclusions • Examples presented are just the tip of the iceberg. • As Internists we mustknow 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.

30. 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 RCTstestinglong-term therapy. • Participate in RCTs for long-term therapy .

31. Questions???