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Journal Scan / Research · September 12, 2018

Diclofenac Associated With Increased Cardiovascular Risk

BMJ : British Medical Journal

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• The authors of this series of 252 nationwide cohort studies in Denmark evaluated the cardiovascular risks of diclofenac initiation. The rate of adverse cardiovascular events among diclofenac initiators was increased by 50% compared with non-initiators, 20% compared with paracetamol or ibuprofen initiators, and 30% compared with naproxen initiators. Even individuals taking low doses had an increased risk of atrial fibrillation/flutter, ischemic stroke, heart failure, myocardial infarction, and cardiac death compared with non-initiators. While the relative cardiovascular risk was highest in people with low or moderate baseline risk, those with the highest baseline risk had the highest absolute risk. The risk of upper gastrointestinal bleeding at 30 days associated with diclofenac initiation was 4.5 times that seen with no initiation and 2.5 times that seen with initiation of ibuprofen or paracetamol. The risk of gastrointestinal bleeding with naproxen was similar to that with diclofenac.

• Diclofenac is associated with an increase in cardiovascular risk compared with paracetamol or other nonsteroidal anti-inflammatory drugs, or no drug use.

 Primary Care

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Peter Lin MD, CCFP

Is Diclofenac Done?

When rofecoxib, a COX-2 Inhibitor, was shown to increase CV events, many of us turned back to the traditional NSAIDs, which blocked both COX-1 and COX-2. The mechanism of the increase in events was simply explained in this fashion. The COX-2 enzyme makes inflammatory prostaglandins in arthritic joints, so blocking it there is a good thing and it helps to reduce pain and swelling. However, COX-2 also lives in the walls of our blood vessels. In the blood vessel wall, the COX-2 enzymes make chemicals that tell platelets not to stick to the blood vessel wall. Therefore, blocking COX-2 in the wall would lead to more clot formation and hence more CV events.

Now the traditional NSAIDs block both COX-1 and COX-2. So, yes, they are also doing bad things on the artery wall, but they also block the COX-1 inside platelets. The COX-1 inside the platelets makes thromboxane, which causes the platelets to form clots. So, by blocking COX-1, clot formation is reduced, which is a good thing. This is how aspirin works. NSAIDs block the vessel wall COX-2, which is bad; but, they also block the COX-1 inside the platelet, which is good. So, overall, there is still balance, no increase in blood clot formation and therefore no increase in CV events.

The only problem is that we assumed that NSAIDs blocked COX-1 and COX-2 equally. Unfortunately, that is not the case. Diclofenac blocks COX-2 more than COX-1. Hence, there is an imbalance in the wrong direction, more clots are formed, and more CV events occur. On the other hand, naproxen and ibuprofen block more COX-1 than COX-2; hence, they do not cause more clots or CV events because blocking COX-1 tells the platelets not to clot. Therefore, diclofenac should do worse than naproxen or ibuprofen in terms of CV events.

However, this is very difficult to prove using a clinical trial. It is unethical to put people on diclofenac knowing that it could cause harm. Hence, we need to look at databases where patients are already on diclofenac and compare their data with data of people using other NSAIDs.

This article looked at a massive database in Denmark. The researchers included 1,370,832 diclofenac initiators, 3,878,454 ibuprofen initiators, 291,490 naproxen initiators, 764,781 paracetamol initiators, and 1,303,209 who took nothing. They were all matched by propensity scoring.

The results showed that diclofenac was associated with more events compared with all the other groups. These are the numbers for major adverse cardiovascular events (MACE):

In addition, there were increases in atrial fibrillation or flutter, ischemic stroke, and heart failure. These effects were seen even in patients who had low baseline cardiovascular risk. So, it is not just the sickest who were affected. And even more concerning is that low doses of diclofenac had the same adverse effect as the high doses.

The study authors concluded that diclofenac usage needs to be reduced, it should not be available over the counter, and patients need to be aware of these potential risks when a prescription is given. They also said that diclofenac should not be used as the comparator in clinical trials for new medications because it itself carries an increased risk on its own.