It Ain’t What You Don’t Know That Gets You into Trouble. It’s What You Know for Sure That Just Ain’t So”[i]

Dogma is interesting. It often arises in the absence of unassailable data. Almost all data start as derivatives from imperfect information. This would suggest that these data should then be reconsidered. Sometimes follow up studies, which are hopefully “better”, support dogma. Frequently, they don’t.

Consider the case of an elderly man with carcinoma of the bladder. After two trans urethral tumor resections, he was put on induction intravesicular BCG bladder therapy and then maintenance for a planned total of 3 years of periodic BCG installations.

Recently (about February 2019) a national/worldwide shortage of BCG became apparent, and distribution from Merck changed. There just wasn’t enough BCG to treat everyone with bladder cancer for the full 3 years as the “standard of practice” dictated. The American Urological Association (AUA) then re-evaluated the evidence on duration of maintenance therapy. The review suggested that more than a year of every 3-month maintenance therapy might have very little incremental benefit over one or two years. The incremental benefit of a third year of maintenance therapy was small. In addition, many of the prior AUA recommendations for therapy have a “Level C” certainty[ii]. It appears that the “standard of care” was based on the way that the initial study of BCG as immunotherapy for Non-Muscle Invasive Bladder cancer was performed[iii], without careful analysis of follow up information.

This experience suggests that when a therapy works, practitioners tend to follow the recommendations as they were written. These recommendations were based on an understanding of the biology of an illness at the time they were written. However, as our understanding of the biology of disease becomes clearer, these shifts in understanding might justify another look at treatment. Ideally this would be done with a Randomized Controlled Clinical Trial, but a registry of therapies for disease should be an acceptable second approach to get data that may overturn existing dogma.

There are examples of dogma, sometimes based on early, imperfect data and sometimes based on opinion, that isn’t/wasn’t effectively challenged, in the field of cardiovascular medicine. These include believing that thrombosis was not the cause of myocardial infarction; and believing that revascularization is superior to non-interventional therapy in coronary artery disease.

Intuition would suggest that Coronary Artery Bypass Grafting (CABG), described by Favalaro in 1967, should be lifesaving in patients with CAD. “Common sense” and the VA cooperative trial said that better blood flow to the heart had to prevent MI and death (the VA trial really only said L-main disease was the lesion in which surgery prevented death). Later trials, notably the Coronary Artery Surgery Study (CASS) showed that there was no major mortality benefit[iv].

Later, still working on the theory that an opened artery should be associated with reduced complications of CAD, interventional cardiologists began to preach that the only way to diagnose CAD was with an invasive angiogram[v]. Once an angiogram showed a narrowed coronary artery then a Percutaneous Coronary Intervention (PCI) or Angioplasty should be done to allow normal coronary flow[vi]. This should prevent MI or death. In 2007 a multicenter, randomized, controlled clinical trial to test this theory was performed[vii]. This study, and a long-term follow-up report also failed to show a benefit to interventional restoration of blood flow in the absence of an AMI. There are data that PCI is potentially beneficial when used to treat a patient with AMI, based on a change in understanding of the pathogenesis of AMI.

The clinical diagnosis of heart attack or Myocardial Infarction (MI) was initially synonymous with coronary thrombosis[viii] In the mid 20th concept was challenged by many authors[ix]. It was not until a very brave cardiology group showed that clot was in fact the cause of MI, that a completely new paradigm of treatment of MI – treating a clot in the artery responsible for the problem[x].

There are many other examples of a new look at an old problem which may result in a better understanding of a clinical condition and lead to markedly improved therapies.

In other situations, a new look may prove a therapy, that initially seemed to be beneficial, to in fact be harmful and actually not helpful to patients (often at high financial cost)[xi].

Observations such as these[xii] may lead patients and physicians to a sense of futility and angst. If there is so much medical reversal, how are we ever to know what to do? Here, I think, we need to realize that there is no certainty in almost anything and that we should go with our best assessment of the best available data. If something “new” comes up and overturns a dogma, then we should embrace the new knowledge and adjust our behavior accordingly. We should understand that in general those reporting in the literature are trying to do the best they can for their patients and the public in general. Sometimes what we thought was true isn’t. That’s when we might get into trouble.

 

End Notes:

[i] The actual source of this statement is evidently unknown: Mark Twain probably said: “It is better not to know so much than to know so many things that aren’t so.” https://quoteinvestigator.com/2018/11/18/know-trouble/

[ii] Diagnosis and Treatment of Non-muscle Invasive Bladder Cancer: AUA/SUO Joint Guideline (2016): https://www.auanet.org/guidelines/bladder-cancer-non-muscle-invasive-guideline#nmibcrisktable accessed 6/5/2019. This is a review of data to 2014. There are 254 citations to the medical literature and disclaimer at end
They use Strength of Evidence statements: A-High; B-moderate and C-low. If no good evidence, then they  labeled as: Clinical Principles and Exert opinion. “The 38 statements created vary in level of evidence,  but none include Level A evidence, and the majority are Level C evidence”

Solsona, E.: Re: Final Results of an EOETC-GU Cancers Group Randomized Study of Maintenance Bacillus Calmette-Guerin in Intermediate – and High-risk Ta, T1 Papillary Carcinoma of the Urinary Bladder: One-third Dose Versus Full Dose and 1 Year Versus 3 years of Maintenance: European Urology, 2014, 65, 847-848: https://doi.org/10.1016/j.eururo.2013.12.034 accessed 8/27/2019

[iii] Morales, A; Eidinger D; BruceA.W. : Intracavitary Bacillus Calmette-Guerin in the Treatment of Superficial Bladder Tumors: J Urol, 1976; 116; 180-183.
This study was done with 6 weeks of “Induction intravesical therapy and then 3 year follow up. The authors admit that “the regimen is arbitrary …” (p894)   There were no recommendations about “maintenance therapy”

[iv] There were many CASS trials. An initial two were published in 1983: CASS Study Group: Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery. Survival data. Circulation. 1983;68:939-50. https://www.ahajournals.org/doi/abs/10.1161/01.CIR.68.5.939   https://doi.org/10.1161/01.CIR.68.5.939 accessed 8/20/2019 and Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery. Quality of life in patients randomly assigned to treatment groups.: Circulation. 1983;68: 951–960:   https://doi.org/10.1161/01.CIR.68.5.951 accessed 8/20/2019 both showed minimal if any mortality or symptomatic benefit from CABG. Follow up research has not refuted any of the initial data.

[v] Any other diagnostic assessment of CAD was “70 cm from the truth” (an angiographic catheter was approximately 70 cm long)

[vi] This line of reasoning was dubbed, by many, “the occulostenotic reflex” – if you see a narrowing (stenosis), “fix” it.

[vii] In the early 20th Century, it was considered unwise to propose, let alone perform such a study. Nonetheless, the study was done, under the Acronym COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation). This study and a subsequent one looking at longer term (8 years) failed to show that Angioplasty, in patients with stable coronary disease, prevented death or heart attack

Bowden, WE; O’Rourke, R.A.; Teo, KK; et al: Optimal Medical Therapy with or without PCI for Stable Coronary Disease: N Engl J Med 2007; 356:1503-1516: DOI: 10.1056/NEJMoa070829

Followed 8 years later by
Sedlis, SP: Hartigan, PM; Teo, KK: et al: Effect of PCI on Long-Term Survival in Patients with Stable Ischemic Heart Disease. : N Engl J Med 2015; 373:1937-1946: DOI: 10.1056/NEJMoa1505532

[viii] The initial clinical description by Herrick in 1910 was entitled “.: Clinical Features of Sudden Obstruction of the Coronary Arteries”: JAMA; 1912; 59; 2015-2020.

[ix] Weisse, AB: The elusive clot: the controversy over Coronary Thrombosis in Mocardial Infarction: J. History of Medicine and Allied Sciences, 2006, 61, 66-78:   https://www.jstor.org/stable/24632276 Subscription may be required

[x] DeWood, MA; Spores, J; Notske, R; et al: Prevalence of Total Coronary Occlusion during the Early Hours of Transmural Myocardial Infarction: New Engl J Med; 1980; 303:897-902 DOI: 10.1056/NEJM198010163031601: 30 refs, 1992 citing articles.
DeWood,MA; Helt,J; Spores, J; et al: Anterior transmural myocardial infarction: effects of surgical coronary reperfusion on global left ventricular function: JACC, 1983, 1, 1223-34

[xi] Frakt, A: Why Doctors Still Offer Treatments that May Not Help – The New York Times Aug 26, 2019: https://www.nytimes.com/2019/08/26/upshot/why-doctors-still-offer-treatments-that-may-not-help.html?searchResultPosition=1

[xii] One other significant reversal came from the WHI randomized study (Manson JE et al.  Menopausal hormone therapy and health outcomes during the intervention and extended post stopping phases of the Women’s Health Initiative Randomized Trials.  JAMA 2013;310:1353-1368.) which changed the habit of recommending hormone replacement therapy, the efficacy of which had been suggested by the observational study of the “Nurses Health Study”: Grodstein, F; Stampfer, M.J.; Manson, J.E.; et al: “Postmenopausal Estrogen and Progestin Use and the Risk of Cardiovascular Disease”: New Eng J Med; 1996; 335; 453-61

 

About Ted

Edward B. J. (Ted) Winslow received an MD from the Faculty of Medicine of the University of British Columbia in Vancouver and an MBA by the Kellogg School of Northwestern University. Before getting his MBA, Ted practiced Cardiology and Internal Medicine at several Chicago institutions (University of Illinois, Veterans West Side, Illinois Masonic, Northwestern Memorial and Evanston Northwestern Healthcare – each one at a time). As a practicing physician, Ted has had experience in managing a medical practice, and implementing the adoption of electronic medical record systems
This entry was posted in CV, General Interest, Guidelines, Health Information, Literature, Policy, Statistics and Decision Making, treatment options. Bookmark the permalink.

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