Saturday, December 24, 2011

Back to the Risks of Prescription Drugs

The latest issue of the Medical Letter (Dec. 12/26, 2011; subscription required) is instructive in reminding us of an important theme behind the ethics of the medicine-Pharma interface. The biweekly newsletter for physicians, supported only by subscriptions and with no industry advertising, reports on two recently approved drugs (dabigatran and dronedarone) that turned out to have greater risks of serious bleeding than had initially been suggested by clinical trials. The newsletter then reviewed another new drug, rivaroxaban, a clotting inhibitor, which in early trials was shown to be somewhat effective (when added to other drugs) in decreasing the risk of future cardiovascular events, but only at the cost of increasing the risk of bleeding into the brain. The Medical Letter experts commented that this puts rivaroxaban in the same category with dabigatran and dronedarone, making one suspect that as more experience is gained, more will come to light about the actual risks of serious bleeding.

These reviews of new drugs reminded me of the fact I have previously blogged about (, courtesy Dr. Donald Light’s important book, The Risks of Prescription Drugs. Dr. Light has reviewed data that indicate that each year, more than 100,000 Americans die of the adverse reactions from prescription drugs, properly prescribed in hospitals. That is, deaths from overdoses and due to errors in prescribing are not included in this total. If accurate, that would make adverse reactions from prescription drugs roughly the 4th largest cause of death in America. And those data exclude all deaths that might occur outside of hospitals.

I have to admit that when I first read that figure, I did not believe it, and I imagined that critics would come forward with different calculations to show that Dr. Light’s results were too high. So I consider it important that no such critics have, to my knowledge, come forward; and Dr. Light informs me that to the extent that he can double-check these calculations, they still appear to be valid, and have been buttressed by more recent studies. If anything, alternative methods of estimating the numbers (there are no direct data available that would give a precise figure) would lead to even higher totals. He also reminded me that the AARP featured these figures in their September magazine, warning about risks of prescription drugs: prescription drugs#pg14

Bear with me for some comments. We already put the American public at high risk of bad things happening to them when we prescribe drugs. Yet the Medical Letter shows that we persist in rolling out new drugs that add even more to the risks.

Pharmapologists will immediately protest that these risks are nothing compared to the wonderful benefits of all these new wonder drugs. So let’s think about those benefits for a minute. Let’s consider the new kid on the block, rivaroxaban, as one example. This drug (brand name Xarelto, manufactured by Janssen/Johnson & Johnson) is an anti-platelet agent (like low-dose aspirin) and is indicated for patients at high risk for blood clots that could cause strokes, heart attacks, and other bad stuff. Patients at that level of risk are typically now treated with two drugs, aspirin and clopidogrel (Plavix). So the research studies on the new drug compared patients taking those other two agents, plus placebo, with those taking the other two agents plus rivaroxaban.

When that comparison was made, the combined bad outcomes (death, heart attack, or stroke) happened in 9.1 % of those taking the three-drug combo (at the lower tested dose of rivaroxaban) compared to 10.7% of those on the two older drugs only. That calculates as best as I can tell to a number-needed-to-treat of 62. That is, you’d have to give 62 people the 3-drug combo for 2 years to prevent one case of death, heart attack, or stroke, in excess of what would happen with just two drugs only. At that dose of rivaroxaban, for every one person who avoided a bad event, another one would suffer a serious (but in this study, non-fatal) brain-bleed-type stroke.

Keep two things in mind. First, the advocates of rivaroxaban are proposing that we take what’s now a 2-drug combo and turn it into a 3-drug combo for treatment of the indicated conditions. We know that the more different drugs you’re taking, the greater the chance of adverse reactions. Second, these are the early data on the efficacy and safety of rivaroxaban. Recall John Ioannidis’s important work showing that we can bet dollars to donuts that the earliest studies of a new drug will show a substantially higher success rate, and a lower adverse-event rate, than the totality of all studies performed over a number of years (see previous post,

To summarize, the US pharmaceutical industry, its pipeline running dry of really good drugs that are truly a major advance over existing drugs, is now busy flooding the market with drugs that offer very slight advantages and only at the cost of serious risk of harm. The total public health impact on the American public is increasingly negative, as Dr. Light’s figures indicate.

I am reminded of the old Harry and Louise ads, funded by the US private health insurance lobby to kill the Clinton health reform plan back in 1993-4. The couple sitting at their kitchen table, after listing all the terrible things that would happen if health reform was enacted, shook their heads and intoned, “There has to be a better way.” I think the same might be said of the way we discover, approve, and market new drugs today.


Anonymous said...

The FDA recently announced that it has initiated a safety review of dabigatran because of adverse event reports of bleeding. My understanding is that when someone who is on warfarin has bleeding, there is a way to reverse the anticoagulant effect. With dabigatran there is no way to reverse it.

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Insane Amp’d said...

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