Tuesday, July 2, 2013

Getting to the heart of the CoQ10 drug test

Jul 01, 2013

By Andy Ho Senior Writer

A READER whose father suffers from chronic heart failure sent me several media reports about a supplement called co-enzyme Q10 (CoQ10).

What heart failure entails is the heart failing as a pump: it no longer pumps blood around the body as well as it used to. This is usually caused by damage to the organ from a heart attack or untreated hypertension. The patient is breathless, exhausted and coughing a lot, while his ankles or even the belly may be swollen.

A report of a trial first begun in 2003 was presented at the European Society of Cardiology conference last month that showed CoQ10 improving heart failure survival rates dramatically.

The conference paper had not yet been peer-reviewed or published. But the researchers were boldly claiming CoQ10 should be given to all heart failure patients now. This garnered much media coverage and gave false hope to many patients and their families.

The study took a decade to finish and involved several medical centres located in many countries. Its researchers randomised 420 heart failure patients of the severest variety into two groups. While all were on medication for heart failure, one group was given CoQ10 and the other a placebo.

Each patient was followed up for two years only. Annually, 9 per cent of those on CoQ10 died from whatever cause compared to 17 per cent of those on the placebo.

Those on CoQ10 were also less likely to die of heart failure or require hospitalisation. In the CoQ10 group, 14 per cent had a major cardiovascular event like a heart attack or stroke compared to 25 per cent of those on the placebo. All percentage differences between the two groups were highly significant statistically.

But these stellar results are questionable. First, patients were followed up for only two years, yet the trial took over 10 years to complete. With an eventual total of only 420 patients, subjects must have been difficult to recruit or often dropping out.

Note that it began a decade ago, and some heart medications used then may no longer be considered optimal now. So any drug interactions that might have mattered may no longer apply to today's heart failure patients.

For these frightfully ill patients, an annual mortality rate of 9 per cent on CoQ10 seems implausibly low. When we look at the absolute numbers for both those on CoQ10 and those on the placebo, only 18 died in either group. So this was a tiny study that took a long time to do and was likely too "underpowered" to detect differences in death rates between the two groups: the small absolute number of deaths likely caused any estimate of risk reduction by CoQ10 to be exaggerated.

Of course, the randomised design of this research with a control group on a placebo is what good studies use. Called randomised controlled trials (RCTs), this design may help overcome researcher and subject bias. Today, RCTs are supposed to offer the best evidence for drug effectiveness. Unfortunately, any treatment that achieves some degree of statistical significance in an RCT is quickly regarded as effective - even if what may be known about the drug's chemistry and the disease's biology make it scientifically implausible for the drug to work in that condition.

In the case of CoQ10, the question to ask then is why it would be biologically helpful in heart failure patients. The study's lead scientist claimed that it "corrects a deficiency in chronic heart failure".

But there is usually CoQ10 deficiency in heart failure only if the patient is also taking statins. These are drugs used to treat raised cholesterol levels, a problem many heart patients may also have. But high cholesterol levels per se have no direct relationship with and are not a cause of heart failure.

It has been established in several trials that statins do tend to reduce the amount of CoQ10 in the body by 30 per cent to 40 per cent.

Incidentally, these statin trials have also established that those heart failure patients who also take statins don't fare any worse than heart failure patients who aren't also on statins because their cholesterol levels were normal to begin with.

That is, critically, statin studies have long established that statins don't worsen the cardiac status in heart failure patients.

Statins - and thus reduced CoQ10 levels - have no causal relationship with how the heart works as a pump.

Now, if reduced CoQ10 levels don't have a biological relationship with the heart failing as a pump, there is no reason why replenishing those levels with CoQ10 pills should improve one's cardiac status in heart failure.

This is not to say that CoQ10 pills are hazardous to heart failure patients. Indeed, there have already been many other trials conducted over the decades for CoQ10 in heart failure. (It has been used routinely for heart failure patients in Japan for decades.) But these studies have usually been small and badly done. Still, they consistently show CoQ10 to be quite harmless: diarrhoea is its most commonly noted side effect in some cases.

To recap, whatever is known about the biological behaviour of CoQ10 in heart failure is not consistent with what this RCT claims. This is crucial: to study any drug with an RCT, it ought to be first scientifically plausible that it actually works for that disease condition.
Before doing an RCT on any drug, its "prior probability" of effectiveness must be scientifically reasonable given what is known about the disease's biology and the drug's chemistry.

Unfortunately, many RCTs are nowadays conducted without insisting on "prior probabilities". Instead, the research enterprise has become a pursuit of statistical significance. The solution to this wrong-headed approach is to factor in biology when interpreting statistics.

So even if your doctor says that RCTs support prescribing CoQ10 for heart failure, what she is saying is scientifically implausible anyway. Still, the CoQ10 pills probably won't harm you either - except that they do cost a pretty penny.

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