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clinical trials

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.

Beyond trials and looking to prevention. Notes from AHA 2011

Ami Banerjee
Last edited 15th November 2011

Since the early trials of beta-blockers and thrombolysis, or “clot-busting” drugs, in cardiovascular disease, the American Heart Association Scientific Sessions and other international cardiology meetings have been dominated by highly-anticipated “late-breaking” or “hot trials” sessions. During these talks, thousands of conference attendees would clamour to hear the results of trials of new drugs reported for the first time. As well as being highly talked about, they greatly influence projections of how the drug will perform in the real market: akin to a stockmarket floor for pharma. Today new drug trials are still by the dozen, but difficult economic times, increased regulation of pharma and wider and quicker dissemination of results may be changing the role of these sessions.

Aside from the trials, three messages are coming through loud and clear from this year’s meeting in Orlando. First, although the best-attended sessions are still the trials of new interventions and drugs for the range of cardiovascular disease, the number of talks devoted to primary prevention and primordial prevention is growing. In other words, prevention of the development of disease and prevention of the development of risk factors of disease, respectively

Second, there is a shifting focus on risk factors as continuous exposures over the whole lifespan. For example, we have talked about “pack-years” of smoking for a long time, i.e. an individual’s lifetime exposure to cigarette smoke. Rather than looking at arbitrary cut-offs for risk factors such as hypertension or high cholesterol, it may make more sense to look at the burden of that risk factor over their lifespan, and in combination with other risk factors.

Third, in the aftermath of the September UN high-level meeting, there is an increasing recognition of the global health aspects of heart disease and stroke. In a session chaired by Professor Sir Magdi Yacoub, eminent cardiac surgeon and long-term activist for improved health services for heart disease in low-income countries, a researcher from Mozambique showed the huge disease burden how feasible screening for common heart diseases can be, even in rural settings.

All three of these changes are welcome and signal gradual, encouraging paradigm shifts among both researchers and health professionals to look at the bigger picture of prevention and population approaches to cardiovascular disease.

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.

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