Weighing up benefit and harm -net clinical benefit and subgroup analysis
The Hippocratic oath originally included the harm and good that doctors and their prescribed treatments can cause. The biggest challenge in today’s clinical practice is not much different. With increasing numbers of trials of different drugs in different patient groups with different comparison groups, how are patients and doctors ever going to see the wood from the trees? How do we make judgments about which drug to use in which situation?
NICE was set up in 1999 in order to help in these difficult matters. Broadly speaking, it looks at current trial evidence and uses the metrics of “cost-effectiveness” to decide whether to fund drugs and treatments in the NHS. It uses “quality-adjusted life years” (the ‘QALY') to measure effectiveness and then calculates the cost per QALY gained for a given drug. A drug must be effective in treating disease but the cost of the benefit must be below a certain threshold, usually £20000-30000 per QALY gained
One problem is that in trials, we tend to focus on benefits and not harms. Another problem is that the performance of drugs in different patients, even for simple characteristics like age and sex and poorly defined in many trials. Even more importantly, trials often do not report their outcomes based on the disease risk of the patients involved. Therefore we end up “painting all patients with one brush”. This has obvious problems. Cost effectiveness analysis is only as good as the trials which are studied and if those trials do not report outcomes (good and bad) properly, then analysis is difficult.
Atrial fibrillation (AF) is a heart rhythm problem which causes increased risk of stroke. Warfarin has been established as a safe treatment for over 50 years and reduces risk of stroke. However, it does lead to increased risk of bleeding, including intracerebral bleeds. Therefore, a way of quantifying the overall benefit of warfarin is to directly weigh up the risk of stroke and the risk of intracerebral bleeds as a “net clinical benefit”, as proposed by Singer and his colleagues in 2009. They reported that “Expected net clinical benefit of warfarin therapy is highest among patients with the highest untreated risk for stroke, which includes the oldest age category.” In other words, we should use the drug in the patients with the highest chance of benefit from the drug, or the highest chance of the adverse outcome (intracerebral bleeds).
Currently 3 new drugs (dabigatran, apixaban and rivaroxaban) have been evaluated in trials as alternatives to warfarin in the setting of AF. Each of these trials looks at different patients and uses different comparisons. In a recent analysis, we used data from the Danish National Patient registry to work out the net clinical benefit of these drugs at different levels of risk of stroke (potential benefit) and bleeding (potential harm) compared with warfarin. We also calculated the number of patients needed to treat and harm for each drug at each level of risk. Although, this is a modelling exercise, this type of analysis is needed in order to look at all the drugs side by side, using the best evidence we currently have. This idea of “net clinical benefit” could also be used in other disease areas in order to quantify to both health professionals and patients how good or bad a treatment is.
The growing global health inequality of new drugs and clinical trials
At the European Cardiology Congress in Paris this week, the news is that cardiovascular medicine is still producing tonnes of new research and there are therapeutic advances in all areas from atrial fibrillation and stroke to heart failure and heart attacks. For example, there are 3 new oral anticoagulants (blood-thinning drugs) which offer true alternatives to warfarin for the first time in 50 years. All these drugs have shown superiority in recent trials presented at this meeting- rivaroxaban in ROCKET-AF, apixaban in ARISTOTLE and dabigatran in the RE-LY trial.
Salim Yusuf, arguably one of the most prolific clinical triallists and lead investigator in two of those trials, also presented the results of a different type of study, published in the Lancet this week. The PURE study included over 150000 patients with known coronary heart disease from 17 countries and showed that even in high-income countries. The drug treatments that such patients should be taking are well-established and available very cheaply-aspirin, beta-blockers, ACE-inhibitors and statins. Depressingly, the proportion of patients globally taking these drugs is less than 50% even in rich countries. In Africa, 80% of eligible patients were taking no drugs at all. As Salim Yusuf said, treatment gaps like this in the HIV/AIDS epidemic led to human rights arguments for broadening of antiretroviral treatment and mobilisation of the global health community and governments.
The inequality was also visible at concurrent “Meet the Triallists” sessions. Delegates clamoured to get to the trial update for the ARISTOTLE trial of the novel anticoagulant, apixaban, but I was one of only 20-30 people who heard Salim Yusuf talk about the PURE trial. Global health cardiology is just not sexy enough yet, even in the wake of the UN high-level meeting in September.
You could argue what is the point of all these fancy new drugs if we are failing to get simple, cheap, proven therapies to the people who need them most, even in rich countries. The tsunami of cardiovascular disease hitting all countries is not going to be touched by all the new drugs currently being trialled. We have to get better at translation. More research funders and senior researchers need to lead new trials with global health impact if we are to have any chance of focusing on problems worth researching.
A Risky Business
A great deal of General Practice is essentially about managing risk. Every time a patient walks through your consulting door you are basically thinking “what are the chances of this patient coming to harm from what they are about to tell me?” Some patients will fall into a category of “high risk” needing immediate or quick treatment. Others may have a degree of risk that necessitates either further investigations or monitoring. Or there may be low risk cases which can be assessed, reassured or treated. This is all supposed to happen within 10 minutes.
But how far should we go to convey that risk to our patients and what is the best way to do it? A recent scenario at my practice made me pause for thought. The cardiologists had advised us to have a discussion with a patient on the merits and risks of aspirin versus warfarin for their atrial fibrillation.
How could that conversation go?
“Right Mr X, the cardiologists have written to me and asked me to help you decide between warfarin or aspirin. They mention in the letter that the risk of you now having a stroke is about 6% per year, however aspirin reduces that risk by about 25% but with warfarin there is about a 45% risk reduction. However, the number needed to treat with warfarin is 37, but bear in mind that warfarin increases the annual absolute risk of major haemorrhage by 2%, so it’s up to you, which one would you prefer? ”
“umm…I’m sorry Doctor, I didn’t understand all of that”
“No neither did I”
So how should we explain risk to patients? The 2002 BMJ clinical review “Explaining risks: turning numerical data into meaningful pictures” by Edwards and colleagues is certainly worth a read. More recently, a study in the Annals of Family Medicine also tried to answer the question. The group surveyed 934 consecutive patients drawn from family practitioners’ waiting rooms in Auckland, New Zealand. Patients were asked to rate how much various modes of communicating the benefits of therapy, to their 5-year CVD risk score, would encourage them to take medication daily. The modes offered to them included: relative risk, absolute risk, odds, number needed to treat, and natural frequencies. The same information was presented in 2 pictorial forms (bar graphs and 10 × 10 people charts). Most patients (61.8%) preferred a doctor to give an opinion than to explain using either numbers or pictures. More than half also preferred a pictorial presentation to numbers; and of the numerical presentations patients found relative risk reduction most encouraging, with absolute risk reduction rated second overall and numbers needed to treat (NNT) the least likely to be persuasive to take their medication.
So should this mean to our practice? Remember EBM is the integration of the best clinical practice, personal expertise and individual patient preference. The latter component is dependent upon the patient fully understanding the risks and benefits of treatment so that a shared management plan can be reached. Having an idea of what those risks mean ourselves is the first step but finding the best way to convey it to our individual patients in as simplest way as possible is perhaps the bigger challenge.