Blinding in trials of interventional procedures is possible and worthwhile

Blinding of patients

Blinding means concealing the treatment allocation from patients and any other people involved in the trial who may bias the results of the trial by knowing which groups the patients were randomised to.

Blinding of patients prevents reporting bias in patient-reported measures. For example, it has been demonstrated that non-blinded patients exaggerate the effects size by 0.56 standard deviations and that the effect is even larger in trials on interventional procedures, such as acupuncture^11,12. This bias may be caused by patients’ expectations of treatment effect and information given to them before the treatment¹³. Patients may also report symptoms depending on their “hunches” about treatment being effective or they may give answers they believe are “correct” or expected from them, for example, because it would have been impolite not to report improvement¹¹. Therefore, it has been suggested that patients should be blinded whenever possible¹¹.

Blinding of patients also reduces adherence bias, i.e. patients in the control group not following the protocol/treatment. It may also prevent so called “contamination of the control group”, i.e. seeking additional treatment/help outside the trial and receiving concomitant treatment. Blinding improves patient retention in the trial. Risk of attrition in blinded trials is about 4% whereas in non-blinded trials it is 7%¹¹. Specifically in placebo-controlled surgical trials, subject retention is often reported as “excellent”¹⁴, and in our analysis the withdrawal rate was low (4%) and comparable between the treatment and the placebo arm¹⁵.

Blinding of surgeons

Unlike drug trials, in which the physician gives a tablet prepared somewhere else, the surgeon has to perform a specific procedure considered to be therapeutic; therefore, blinding of surgeons may not always be possible.

There have been attempts to blind surgeons, for example a surgeon inserted a catheter under fluoroscopic guidance and handed over the procedure to a technician who delivered the radiofrequency energy (or not) according to the allocation¹⁶. In other trials, a palatal implant delivery system was prepared by the manufacturer to either contain the implant or not, which allowed for blinding of surgeons^17,18.

Blinding of outcome assessors

In 81% of placebo-controlled surgical trials both patients and assessors were blinded¹⁵. It has been demonstrated that, non-blinded assessors of subjective outcomes cause less bias in trials than non-blinded patients reporting their symptoms¹⁹. Blinding of assessors prevents observer-related bias, detection bias, and the Pygmalion effect. The Pygmalion effect refers to a situation when investigators looking for a particular response are predisposed to interpret the result in a way that shows the response they expect even if it is objectively absent. For example, a study by Hrobjartsson and colleagues demonstrated that non-blinded assessors were over-optimistic and “over-rated” patients in the treatment group rather than “under-rated” patients in the control group²⁰. In some trials the assessment was done by people not involved in the surgery, for example blinded researchers, staff at another hospital that they were operated on at²¹, or by pathologist blinded to the treatment allocation²².

Blinding of caregivers

Apart from blinding patients and assessors, it is important that caregivers and clinical/research staff do not know patient treatment allocation, because their behaviour and attitudes may influence patient responses^23–25. Patient-clinician interaction plays an important role in treatment response, and patients in trials do better as they get more attention and time from clinical staff than patients receiving standard care^26,27. Therefore, the interactions between patients and the trial team should be standardised so that the “treatment context” (similar attention from doctors, expectations, and settings) are comparable between the groups.

Imitation of incision/ surgical access point

If a procedure requires open surgery, then it will leave an obvious mark where the incision has been made, which will have to be imitated in the placebo group. There have been very few trials involving full skin incision, in both the surgical and placebo arms. In the seminal trials on internal mammary artery ligation^31,32 a skin incision was made to expose the arteries in all patients but no ligation was made in the placebo group. Similarly, Guyuron and colleagues used a skin incision to expose superficial nerves and muscles, which were cut during the active surgery but, in the placebo group, the integrity of these structures was maintained³³. Trials investigating transplantation of dopaminergic neurones as a treatment for Parkinson’s disease not only required skin incision but also burr holes in the skull^34,35.

However, most of the published placebo-controlled surgical trials used minimally-invasive methods to access the structure of interest. For example, the placebo procedure involved laparoscopy but without ablation³⁶, endoscopy without radiofrequency energy delivery³⁷, bronchoscopy without radiofrequency energy delivery³⁸, or bronchoscopy without valve placement³⁹. Therefore, most of the studies required a small incision to mimic the portals created during the laparoscopy or arthroscopy, or to mimic the incision through which an intravascular catheter was inserted⁴⁰. Interestingly, Sutton and colleagues used three incisions in both groups so that patients could not tell apart a diagnostic laparoscopy from a laparoscopic surgery; even though the third instrument port was not necessary in the placebo group⁴¹. Trials using endoscopy and bronchoscopy were even easier to blind as natural orifices were used to insert the scope, and the incision or actual procedure site was not visible to patients, caregivers, and assessors.

Simulation of an interventional procedure

Typically, the preparation for the placebo procedure and the active procedure was as similar as possible and immitated the visual, auditory, and physical cues^42–45. In order to mimick the sounds, surgeons were required to talk through the procedure steps⁴⁶, ask for instruments^47,48, use suction⁴⁸ or ask for a laser or other device to be activated, even though it was not used in the placebo group^49–53.

Clinical staff performing the intervention were screened from the patients’ view⁵⁴ either by a surgical drape⁵² or by arranging the operating room in a way that the patient could not see the procedure⁴⁴. In the trial by Stone and colleagues, patients were heavily sedated and wore opaque goggles³⁰. In a trial by Maurer and colleagues, the manufacturer delivered tools that looked identical but did not contain an implant, which allowed for blinding of patients and clinical staff¹⁸.

Surgeons also attempted to immitate sensory cues, for example by manipulating the knee as if the actual arthroscopy were performed⁴⁸, injecting saline to imitate tidal irrigation¹⁴, or by splashing saline on the knee to simulate lavage⁴⁵. In a trial on meniscectomy, surgeons used a mechanised shaver (without the blade) pushing it firmly against the patella to simulate the sensations the patient would experience during the surgery⁴⁸. In a trial on intragastric balloon for obesity, operators manipulated the endoscope as during the balloon insertion to create the sensation of resistance in the stomach⁵³.

Even smell during the surgery was imitated to make the placebo procedure indistinguishable from surgery. For example, in the trial by Deviere and colleagues there were concerns that patients could have known the allocation because the copolymer used in the active arm had a distinct smell⁵⁵. In trials on vertebroplasty, a container with cement was opened during placebo procedure to help with blinding^42,56.

Inactive nature of the placebo

It is important that the procedure used for blinding does not have any therapeutic effect. For example, the results of the vertebroplasty trials^42,56 were criticised because the elements of placebo procedure could have had an effect on the reported pain, namely, a potential pharmacological anaesthesia due to injection of an anaesthetic into the facet capsule and periosteum⁵⁷.

On the other hand, the procedure used for blinding may have diagnostic use, as with diagnostic laparoscopy^36,41,58 or diagnostic laparoscopy with biopsy⁵⁹. In the trial by Sihvonen and colleagues, all participants underwent diagnostic arthroscopy, but only after they had been confirmed to be eligible for inclusion in the trial was the envelope with the assignment opened and the assignment revealed to the surgeon⁴⁸.

Duration of the procedure

Many trials specifically stated that the duration of procedure in the surgical and control arms were matched, either by immitating the elements of the surgical procedure or by keeping all patients in the operation room for the same duration of time^{34,38,45,47,48,60,61}. However, in some trials, the placebo procedure was shortened in comparison to the actual surgery because it was believed it would have been ethically unacceptable to prolong the placebo intervention^49,55.

Additional procedures that may reveal allocation

Interventional treatment often requires additional procedures, such as diagnostic scans or medication to prevent infection^43,56,62, blood clots⁴⁰, transplant rejection⁶³, or epileptic fits³⁵. For example, in the trial by Freed and colleagues, both groups received identical preoperative evaluation, intraoperative sedation and pain control, underwent two PET scans and a MRI scan, and received phenytoin³⁵. In some trials, the same medication was given in both groups, whereas in others unnecessary treatment was omitted or imitated, for example by injecting saline instead of antibiotics⁶⁴.

Standardisation of interventions and care

The active and placebo procedure have to be indistinguishable but they also have to be stable and standardised. Standardisation of the procedure itself may be difficult but is important because surgeons vary in their experience, and gain experience throughout the trial.

Some of the changes observed in a trial may not be related to the treatment or the placebo intervention, but may be caused by the natural course of the disease, spontaneous remissions or fluctuations in the severity of symptoms or regression to the mean^27,65. Some changes may be a result of just being in a trial either because of lifestyle changes that are part of the protocol such as self-monitoring using diaries or avoiding alcohol or due to so called “Hawthorne effect”, which refers to change in the behaviour when people, both patients and doctors, know that they are being observed²⁷. Finally, it has been demonstrated that adhering to a protocol improves the performance of doctors, and that patients who adhere to treatment regimes have better outcomes⁶⁶. Therefore, it is important to standardise pre- and post-operative care, and the explanations given to the patients. For example, in a trial by Sihvonen and colleagues all procedures were standardised and recorded on video; the post-operative care was also standardised, and all patients received the same exercise programme and walking aids⁴⁸.

Blinding after the surgery

Most trials blinded the assessors while the surgeon and other staff in the operating room were aware of the group assignment, and did not participate in further treatment, post-operative care or follow-up of the patient^36,48,67. In a trial by Thomsen and colleagues, the post-operative care and assessment was done at a different hospital than the surgery²¹. In a trial by Cotton and colleagues a post-operative care was provided by the referring physician, who was blinded when deciding on treatment, and when this was not sufficient, by the evaluating physician at the study site (who was also blinded)⁶⁷.

Bias specific to surgical trials

There are other types of bias that are specific to surgical trials. For example, in trials on upper gastrointestinal tract bleeding, the endoscopic procedure was not performed if the rate of blood loss was too fast, or the endoscopy was judged to be life-threatening and posed an unacceptable risk^68–70. In other trials, some patients were excluded because they could not tolerate endoscopy, or due to anatomical conditions that made the surgery impossible to carry out (laser could not be aimed at the bleeding arteries)⁷⁰. Alternatively, some patients were not included in a trial because they were no longer eligible, for example because the bleeding had stopped⁷⁰ or they no longer reported the symptoms on the day of the study⁷¹.