Evidence-based surgery:Are we there yet?

Ivan Lester Memorial LectureCairns, 30 October 2014

Robyn McDermott

Ivan Lester and staff, Cairns Hospital, 1950’s

Tonight… 3 stories of surgery

• The value of reflection• The special case of surgery• Doing harm – how can we know?• Doing good – where is the evidence?• Serendipidy in Medicine – the case of bariatric

surgery• Evidence vs Fashion vs Fashionable Evidence

Why evaluate?

• First, do no harm• Second, is it effective? (Levels of evidence

and the ethics of sham procedures in trials)• Third, is it cost-effective?• Fourth, who benefits and who pays?

Equity considerations

Procedures are different to drugs

• Consistency – quality control (surgeon)• Reproducibility – contextual factors (hospital

facilities, patient selection)• Scalability – what is the “right” number?• Reversibility – can be hard to revise/remove• Implications for RCTs – placebo effects of

sham surgery• Innovation vs safety

“Prefrontal leucotomy”Egas Monitz, Portuguese neurologist, is credited with inventing the lobotomy in 1935, for which he shared the Nobel Prize for Medicine in 1949.

Walter Freeman, Neurosurgeon, developed the “transorbital lobotomy” in 1945, as an office procedure which involved using an “orbitoclast”, a modified ice pick, inserted through the patient's eye socket using a hammer. The instrument was moved side-to-side to “separate the frontal lobes from the thalamus”.30,000-40,000 performed in the USA in the 50’s and 60’s, finally stopped in 1967.

Used to treat a range of mental illnesses including depression, schizophrenia, bad behaviour, panic disorders…Not based on any real scientific evidenceSignificant harm done to thousands

“Metal-on-metal” hip prostheses

The Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) was established in 1999. The data from the NJRR showed that most MoM implants performed similarly to other types of hip implants, however the revision rate was double. Adverse health outcomes reported due to release of metal (chromium and cobalt) ions and particles from these implants. “At this time, there is insufficient evidence to conclusively demonstrate that MoM hip implants produce side effects beyond those that may occur at the site of implantation. However, metal ions have been reported to be associated with effects on the heart, nervous system, endocrine system and skin.” (TGA)

Total hip replacement where metal is used instead of plastic or

ceramic surfacing: Use peaked in 2007

Levels of evidence required for approval and listing by TGA/PBS

Drugs Devices/proceduresLarge RCTs required for all, meta-analysis of RCTs preferred: All RCTs registered centrally with trials register to avoid publication bias

Only 1% of devices reach the market through the “pre-market approval” process (trial reporting)

Drug trials frequently have a placebo control arm in safety (phase 1) trials

“Sham” surgery (placebo) rarely used

Safety must be demonstrated in small numbers of humans in phase 1 and 2 trials

Innovations are “diffused” in the profession, marketeers solicit clinical opinion leaders

Phase 3 and 4 trials required to maintain safety monitoring independently of the trial investigators and marketers

At best, a register of devices kept institutionally, sometimes centrally (eg joint replacement register)

Post-marketing surveillance is variable PMS variable

Proving effectiveness:Is sham surgery unethical?

Renal artery denervation (catheter-based radio frequency ablation) for Resistant Hypertension: the SYMPLICITY trial (RCT with sham procedure) showed no effect (Bhatt et al, NEJM 2014;370:1393-401)Fetal-tissue transplantation for Parkinson’s disease: RCT of sham twist-drill holes in the forehead found no effect different from placebo (Freeman, 1999)Vertebroplasty (bone cement injected into fractured vertebra for compression fracture) popular in the early 2000’s, however an RCT with sham control procedure found no difference (Buchbinder et al 2009 NEJM)

Procedural placebos appear more powerful than drug placebos:

Example of migraine

Sham surgery for migraine: 58% of patients had a positive responseSham acupuncture for migraine: 38% positive responseOral pharmacological placebos for migraine: 22% positive responseSource: Meissner et al. Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis. JAMA Int Med. 2013; 173: 1941-51

Bariatric surgery for weight loss

Laparoscopic adjustable gastric banding: the gastric circumference is adjusted (narrowed) by a band of plastic material using an inflatable fluid-filled balloon that is connected, via a catheter, to a subcutaneous reservoir.

Roux-en-Y gastric bypass (RYGB): the stomach is divided along the lesser curvature, creating a small reservoir of about 30 ml that is anastomosed to the distal end of the jejunum, which is divided at about 75 cm from the ligament of Treitz

Biliopancreatic diversion (BPD): partial gastrectomy (about 50–60%) and gastroentero-anastomosis. The ileum is then divided 250-cm proximal to the ileocaecal valve and its distal end anastomosed to the resected stomach

The serendipidy of bariatric surgery

Bariatric surgery led to rapid weight loss (mostly sustained), however it also reversed T2DM quickly, prompting a look also at…..• Role of gut peptides,• Impact of changes in gut microflora ecology,

and• Bariatric surgery in T2DM prevention?

Cumulative Incidence of Type 2 Diabetes.

Source: Carlsson LM et al. N Engl J Med 2012;367:695-704.

Bariatric surgery and type 2 diabetes prevention

Lessons from the microbiome project: You are what you eat, and so are the friends that live in your gut.

They digest food and also modulate gut-derived endocrine, neuronal and inflammatory signals.

Source: Matthias H Tschöp, Philip Hugenholtz & Christopher L Karp Getting to the core of the gut microbiome Nature Biotechnology 27, 344 - 346 (2009) doi:10.1038/nbt0409-344

The gut micro biome has a regulatory function on host energy metabolism.

Source: Krajmalnik-Brown R et al. Nutr Clin Pract 2012;27:201-214

Changes in gut microbiota (following high-fat diet or obesity) promote gut permeability, increase metabolic endotoxemia and trigger the development of metabolic disorders

Source: Patrice D Cani , Nathalie M Delzenne Interplay between obesity and associated metabolic disorders: new insights into the gut microbiota Current Opinion in Pharmacology, Volume 9, Issue 6, 2009, 737 - 743

http://dx.doi.org/10.1016/j.coph.2009.06.016

Can a healthy gut microbiome prevent and reverse obesity and T2DM?

• Obesity and type 2 diabetes (T2D) are associated with a profound dysbiosis.

• There are highly significant correlations of specific intestinal bacteria, certain bacterial genes and respective metabolic pathways with T2D.

• Butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii concentrations are lower in T2D subjects.

• This supports the increasing evidence that butyrate, acetate and other short-chain fatty acids (“fibre”) are able to exert profound immunometabolic effects.

• Endotoxaemia, most likely gut-derived has been observed in patients with metabolic syndrome and T2D and appears to play a key role in metabolic inflammation.

Fashion and “EBM”