DRAMATIC TREATMENT EFFECTS: RARE AND READILY RECOGNIZABLE

Only rarely will the evidence be so clear-cut that there is no room for doubt about whether a treatment works.² In such cases the treatment effect is often dramatic and immediate. Take the heart rhythm disorder known as ventricular fibrillation, where muscle contraction in the ventricles (lower chambers) of the heart becomes wildly uncoordinated. This is a medical emergency – death can occur in minutes. The technique of ‘zapping’ the heart with a direct electrical current from a defibrillator applied to the chest is used to restore the heart’s normal rhythm; when successful, the effect is virtually instantaneous.

Other dramatic effects (see also Chapter 6, p70) include drainage of pus to relieve pain from abscesses, blood transfusion for shock caused by severe haemorrhage, and insulin (a hormone produced by the pancreas) for diabetes. Up to the 1920s, patients with diabetes had short lives and suffered immensely, wasting away with uncontrollably high blood sugar levels. Very quickly, the initial results of animal tests led to the use of insulin in patients, with outstanding success – their response was near miraculous at the time. Another example from that era was the use of liver – later shown to be a source of vitamin B12 – for patients with pernicious anaemia. In this then fatal type of anaemia, the numbers of red blood cells gradually fall to disastrously low levels, leaving patients with a ghostly pallor and profound weakness. When these patients were given liver extract they recovered rapidly, and vitamin B12 is now prescribed routinely for this form of anaemia.

Some examples from the beginning of this century highlight similarly dramatic results.

MODERATE TREATMENT EFFECTS: USUAL AND NOT SO OBVIOUS

Most treatments do not have dramatic effects and fair tests are needed to assess them. And sometimes a treatment may have a dramatic effect in some circumstances but not in others.

Although vitamin B12 is undoubtedly effective for pernicious anaemia (see above), dispute continues to this day about whether patients need quarterly or more frequent treatment. That question will only be answered by carefully controlled tests comparing the options. Moreover, whereas the pain relief with hip replacements is dramatic, the relative merits of different types of artificial hip joints are far more subtle, but may nevertheless be important – some may wear out faster than others for example. With laser treatment of portwine birthmarks (see above), there is also still much to learn. Whilst this treatment remains the ‘gold standard’, research continues into why some lesions re-darken after several years, and on the effects of different types of lasers, possibly combined with cooling of the skin.^{9, 10}

And while aspirin substantially reduces the risk of death in patients suffering a heart attack if given promptly on diagnosis, whether taking aspirin to prevent heart attacks and strokes does more harm than good depends on whether patients have underlying cardiovascular disease. The benefits – reduction in the risk of heart attacks, strokes, and death from cardiovascular causes – need to be balanced against the risks – bleeding, especially the type of stroke caused by bleeding into the brain, and bleeding from the gut. In patients who already have cardiovascular disease, the benefits of the drug greatly outweigh the risks. But in otherwise healthy people, the benefits of aspirin do not clearly outweigh the risk of bleeding (see Chapter 7).¹¹

WHEN PRACTITIONERS DISAGREE

For many diseases and conditions, there is substantial uncertainty about the extent to which treatments work, or about which treatment is best for which patient. That doesn’t stop some doctors having very strong opinions about treatments, even though those opinions may differ from one doctor to the next. This can lead to considerable variation in the treatments prescribed for a given condition.

In the 1990s, Iain Chalmers, one of the authors, while holidaying in the USA, broke an ankle and was treated by an orthopaedic surgeon. The surgeon put the leg in a temporary splint, and said that the next step, once the swelling had subsided, would be a lower leg plaster cast for six weeks. On returning home a couple of days later, Iain went to the local fracture clinic, where a British orthopaedic surgeon, without hesitation, dismissed this advice. Putting the leg in plaster, the British surgeon said, would be wholly inappropriate. In the light of this obvious professional uncertainty, Iain asked whether he could participate in a controlled comparison to find out which treatment was better. The British surgeon answered that controlled trials are for people who are uncertain whether or not they are right – and that he was certain that he was right.

How can such a pronounced difference in professional opinion come about, and what is a patient to make of this? Each surgeon was certain, individually, about the correct course of action. Yet their widely divergent views clearly revealed uncertainty within the profession as a whole about the best way to treat a common fracture. Was there good evidence about which treatment was better? If so, was one or neither surgeon aware of the evidence? Or was it that nobody knew which treatment was better (see Figure).

What should a doctor do?

Perhaps the two surgeons differed in the value they placed on particular outcomes of treatments: the American surgeon may have been more concerned about relief of pain – hence the recommendation of a plaster cast – while his British counterpart may have been more worried about the possibility of muscle wasting, which occurs when a limb is immobilized in this way. If so, why did neither surgeon ask Iain which outcome mattered more to him, the patient? Two decades later, uncertainty continues about how to manage this very common condition.¹²

There are several separate issues here. First, was there any reliable evidence comparing the two very different approaches being recommended? If so, did the evidence show their relative effects on outcomes (reduced pain, or reduced muscle wasting, for example) that might matter to Iain or to other patients, who might have different preferences to his? But what if there was no evidence providing the information needed?

Some clinicians are clear about what to do when there is no reliable evidence about the effects of alternative treatments and are prepared to discuss this uncertainty with patients. For example, one doctor who specializes in caring for people with stroke, commented that, although research evidence shows that his patients would fare better if cared for in a stroke unit, it remained uncertain – for many types of patients – whether they should receive clot-busting drugs (see also Chapter 11, p139). When discussing treatment options with his patients he explained that these drugs may do more good than harm, but they may – for some patients – actually do more harm than good. He then went on to explain why, talking to a patient for whom the balance of risk and benefit was unclear, he felt he could only recommend this treatment for them within the context of a carefully controlled comparison, which should help to reduce the uncertainty.¹³ Uncertainties about several aspects of clot-busting drugs persist.¹⁴

ADDRESSING UNCERTAINTIES ABOUT THE EFFECTS OF TREATMENTS

Where do we go from here? Clinicians need to be able to draw on resources that provide the best current evidence about a treatment, taken from collective experience and systematic reviews of any reliable research studies that exist. If, after doing this, they find that uncertainty remains about a treatment, they need to be prepared to discuss this with their patients and to explain why this is so. Patients and clinicians can then discuss the options together, taking into account patient preferences. These discussions may raise further uncertainties that need to be acknowledged and addressed. Only by recognizing together that uncertainties still exist, can steady progress be made towards making treatments more appropriate and safer. Uncertainty is therefore a prerequisite for progress, not an admission of ‘defeat’. This positive attitude to addressing uncertainties is now reflected in some professional guidance. In the UK, the General Medical Council’s latest version of its Good Medical Practice guidance instructs doctors that, as part of maintaining and improving their performance, they ‘must help to resolve uncertainties about the effects of treatments’.²¹ To do this, patients and clinicians must work together to design better research (see Chapter 11).

PROVIDING TREATMENT AS PART OF A FAIR TEST

So what should happen when there is important uncertainty about the effects of new or old treatments that have not been properly evaluated? An obvious answer is to follow the example of the doctor caring for his stroke patients, as we described above: address the uncertainty by offering inadequately assessed treatments only within the context of research that has been designed to find out more about both their wanted and unwanted effects.

A medical ethicist put it this way:

‘If we are uncertain about the relative intrinsic merits of any [different] treatments, then we cannot be certain about those merits in any given use of one of them – as in treating an individual patient. So it seems irrational and unethical to insist one way or another before completion of a suitable trial. Thus the answer to the question, “What is the best treatment for the patient?” is: “The trial”. The trial is the treatment. Is this experimentation? Yes. But all we mean by that is choice under uncertainty, plus data collection. Does it matter that the choice is “random”? Logically, no. After all, what better mechanism is there for choice under uncertainty?’²²

Providing treatments as part of fair tests can help to make a profound difference to outcomes for patients. The story of childhood leukaemia provides a very dramatic example of this. Until the 1960s, virtually every child with leukaemia died soon after the diagnosis had been made. Now about 85 children out of 100 survive. This has been achieved because most children with leukaemia have participated in randomized trials comparing the current standard treatment with a new variant of that treatment.²³ For most children with cancer, therefore, the best treatment option is chosen by participation in such trials.

If no such trial is available, at the very least the results of using new and untested treatments should be recorded in a standardized way – for example, by using a checklist of items including the laboratory or other tests that will be used to diagnose a condition and the tests that will be done to assess the impact of the treatment. The plan of investigation could also be registered in a database, as should happen for clinical trials (see Chapter 8). By doing this, the results can contribute to the body of knowledge for the benefit of the patients receiving the untested treatment and patients everywhere. Huge sums of money have already been invested in healthcare IT systems, which could readily be used to capture this information for the benefit of patients and of the public (see also Chapter 11).²⁴

There will have to be changes if uncertainties about the effects of treatments are to be addressed more effectively and efficiently. We discuss some of these – particularly the greater involvement of patients – later in the book (see Chapters 11 and 12). However, there is a particular issue – we touched on it above – that we want to emphasize here. When there is insufficient information about the effects of a treatment, knowledge can be increased by ensuring that clinicians only offer it within the context of a formal evaluation until more is known about its value and possible disadvantages. Yet some prevailing attitudes, including systems of research regulation (see Chapter 9), actually discourage this risk-limiting approach.

The problem vexed a British paediatrician over 30 years ago when he pithily observed that he needed permission to give a treatment to half his patients (that is, to find out about its effects by giving half the patients the new treatment and half the existing treatment in a controlled comparison), but not if he wanted to give the same treatment to all of them as a standard prescription.²⁵ This illogical double standard still pops up repeatedly and discourages clinicians who want to reduce uncertainties about the effects of their treatments. The overall effect is that health professionals can be deterred from generating knowledge from their experiences in treating patients. As the American sociologist Charles Bosk once remarked: ‘anything goes, as long as we promise not to learn from the experience’.

Being able to explain uncertainty clearly demands skills and a certain degree of humility on the part of doctors. Many feel uneasy when trying to explain to potential participants in a clinical trial that no one knows which treatment is best. But the public’s attitude has changed: arrogant doctors who ‘play God’ are increasingly given short shrift. We need to focus on training doctors who are not ashamed to admit they are human and that they need the help and the participation of patients in research to provide more certainty about choices of treatments (see Chapters 11 and 12).

The main stumbling block for many clinicians and patients is lack of familiarity with the features of fair tests of treatments, an issue we tackle next (see Chapter 6).