Understanding Medical Controversies: When Evidence and Theory Collide

1. Understanding Medical Controversies:When Evidence and Theory Collide Tom Tape, MD, FACP September, 2012

2. Questions to consider… • How do we know whether what we are doing for the patient is right or wrong? • Where do our “standards of practice” come from?

3. Example: Bloodletting • Based on the prevalent ideas about disease: • Humoral imbalance (plethoras) • Tainted blood

4. Example: Vitamin C for Scurvy • Based on empirical evidence from a clinical trial of treatment with various acids: • In 1747, James Lind tried 6 treatments on 12 sailors with scurvy. • Only the 2 getting citric acids improved.

5. The Philosophy of Truth… • There is more than one way to evaluate the truth of a proposition. • CoHerence: It is true because it makes sense. • It is logical • It conforms to our theory • CoRRespondence: It is true because it is empirically correct. • It is supported by evidence

6. Coherence reasoning guides research and clinical judgment • Coherence drives much of modern biomedical research: • First identify the cause of a disease, then design a rational therapy. • Coherence-based reasoning seems to “explain” the cause of disease: • Peptic ulcers attributed to stress and acid. • Tension headaches attributed to muscle spasm. • Both commonly held beliefs are not true.

7. Correspondence criteria supports Epidemiological studies & Clinical trials • For example: Framingham heart study • Epidemiological risk factors of Cardiac disease • Hypertension, cholesterol, diabetes, smoking, etc. • Risk factors are correspondence-based without effort to understand why they cause disease. Kannel WB, et al. Factors of risk in the development of coronary heart disease-six year follow-up experience; the Framingham study. Ann Intern Med. 1961;55:33-50.

8. Evidence-based Medicine (EBM) • EBM became widely known in the 1990s. • Largely correspondence-based: • Conscientious, explicit and judicious use of current best evidence from systematic research to make decisions about the care of individual patients. • De-emphasized intuition, unsystematic clinical experience, and pathophysiologic rationale. • EBM polarized the medical profession. Sackett DL, et al. Evidence based medicine: what it is and what it isn’t. BMJ 1996;312:71-2.

9. A current medical controversy Atrial fibrillation: How should it be managed? From: Frye WB. Tracing Atrial Fibrillation – 100 years. New Engl J Med. 2007;255:1412-1414.C

10. Atrial fibrillation (AF): Key concepts of coherence model • Chaotic electrical activity in atria. • Irregular and often rapid ventricular response. • Loss of atrial contraction. From:Zimetbaum P. Amiodarone for atrial fibrillation. New Engl J Med. 2007;236:935-41.

11. Until very recently, the modern management of AF was based on coherence: • Rhythm control strategy: • Restore normal sinus rhythm with electrical cardioversion and/or antiarrhymic medications. • Coherence rationale: • Slow, regular rhythm optimizes pumping action. • Contracting atria help fill ventricles.

12. Correspondence Approach to AF • Observation that patients seem to tolerate slow AF with few or no symptoms. • Hypothesis that control of heart rate might be good enough treatment for AF • Rate control strategy: • Slow the ventricular response by giving drugs that block conduction from the atria to the ventricles.

13. AFFIRM Trial (2002) • 4060 patients randomized to either: • Rhythm control strategy • Rate control strategy • Outcomes measured: • Death • Hospitalizations • Adverse drug effects • AFFIRM Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. New Engl J Med. 2002;347: 1825-1833.

14. AFFIRM Trial Results • Rhythm control no better than rate control. • Higher mortality trend with rhythm control. • More hospitalizations with rhythm control. • Many more adverse effects with rhythm control. • Authors conclude: • “None of the presumed benefits of rhythm control …were confirmed in this study.”

15. Reaction to the AFFIRM Trial • Accompanying editorial: • “An attempt to restore sinus rhythm is still appropriate, although it can no longer be deemed imperative.” • Skeptics cite “design flaws” in AFFIRM; many continue to favor rhythm control. • But…five subsequent correspondence trials also show detrimental effects of rhythm control.

16. Cardiologists cling to coherence “Nature has equipped the human heart with a complex electrical system for the purpose of coordinated propulsion of blood under a variety of physiologic conditions. Considerable effort is expended by the heart to maintain sinus rhythm. Cardiac electrophysiologists…are frustrated by the conundrum that atrial fibrillation is associated with increased morbidity and mortality, yet attempts to prove that a strategy to maintain nature’s rhythm has a favorable effect on patients have been met with one setback after another.” Cain ME. Rhythm control in atrial fibrillation—one setback after another. New Engl J Med. 2008;258-2725-7

17. A Recent Example: Vitamin D • Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women • Sanders, KM et al. JAMA. May 12, 2010 303:1815-22 • Hypothesis: Vitamin D supports bone health. • Randomized 2256 women 70 years & older to receive high dose vitamin D or placebo for 3-5 years. • Fall rate and fracture rate were increased in the women taking vitamin D.

18. An editorial questions the findings • “The biological plausibility of these findings remains speculative.” • “…vitamin D may improve physical performance, reduce chronic pain, and improve mood in older adults. Such benefits may have led to increased mobility and opportunity for falls…” • “Another plausible explanation is that supplemental [vitamin D] may have decreased the rate of wintertime infections.” • Dawson-Hughes B & Harris SS. High-dose vitamin D supplementation: Too much of a good thing? JAMA May 12, 2010 303:1861

19. Another Recent Example: FEAST Study • Mortality after Fluid Bolus in African Children with Severe Infection • K. Maitland et al. NEJM 2011;364:2483-95. • Premise: “Rapid, early fluid resuscitation in patients with shock, a therapy that is aimed at the correction of hemodynamic abnormalities, is one component of goal-driven emergency care guidelines.”

20. Fluid Expansion as Supportive Therapy • Random allocation of 3170 children to (1) Albumin bolus, (2) Saline bolus, or (3) No bolus • “The results of this study challenge the importance of bolus resuscitation as a lifesaving intervention…for children with shock….”

21. Editorial comment regarding FEAST • “The results of the FEAST trial…make it imperative that we reappraise the fundamentals.” • “We can only speculate on the mechanisms…” • Interruption of catecholamine-mediated host defense responses by rapid increase in plasma volume. • Exacerbation of capillary leak in patients who are susceptible to intracranial hypertension or pulmonary edema. • “Fluid resuscitation is such a fundamental intervention in acute medicine that these results indicate that further high-quality research is urgently required to define appropriate practice….” • J. Myburgh. NEJM 2011;364:2543-2544

22. Physicians lack insight about the coherence – correspondence distinction. • Coherence and correspondence are not part of the medical vocabulary. • Physicians using the two different approaches don’t understand why their viewpoints differ. • When the two approaches produce conflicting results, coherence often becomes the favored strategy.

23. Why do we cling to coherence? • Much of modern medical research is coherence-based. • Coherence-based theories and correspondence-based evidence are often concordant. • We are drawn to explanations that “make sense.”

24. Paying attention to conflict can advance the field in surprising ways. • Coherence approach to new drug development: “Rational drug design” • Sildenefil designed to relax smooth muscle in blood vessels in hopes of lowering blood pressure. • Correspondence trials found little effect on BP. • But, subjects did not wish to surrender their supply of unused study drug! • Further coherence-based work has radically changed our understanding of Erectile Dysfunction. Kling J. Modern Drug Discovery. 1998:1:31-8.

25. Summary points • Coherence / correspondence terms are essentially unknown to medical professionals. • Controversies in the field often involve a coherence vs. correspondence debate. • Understanding and applying both approaches can both reduce controversy and advance the field.