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.