Dr. John Day, Cardiologist

Is Diltiazem Dangerous to Use with Eliquis or Xarelto?

A recent study involving 204,155 Americans with atrial fibrillation just concluded that using ditiazem with either Eliquis (apixaban) or Xarelto (rivaroxaban) was potentially dangerous due to increased bleeding risks. Is this really the case? And if it is, what steps should you take if you have been prescribed these medications? Keep reading to find out more.

What is Diltiazem?

The cardiac medication diltiazem also goes by the brand names of Cardizem, Tiazac, Cartia, Dilacor, Matzim, Taztia, and Dilt-XR.  Diltiazem is the second most commonly prescribed medication in the US to slow the atrial fibrillation (AFib) heart rate, right after metoprolol. Apart from regulating the AFib heart rate, diltiazem also helps in lowering blood pressure. For those with AFib, diltiazem can greatly reduce symptoms and may also lower the risk of heart failure when the heart beats too fast from AFib.

What are Eliquis and Xarelto?

Eliquis and Xarelto are the top two blood thinners for AFib in the US. Both Eliquis and Xarelto are factor Xa inhibitors. They’re popular because they’re safe, easy to use, and don’t require a lot of monitoring or check-ups.

What is the Drug Interaction Between Diltiazem and Eliquis/Xarelto?

The interaction between diltiazem and Eliquis or Xarelto revolves around the enzyme system called cytochrome P450. Diltiazem can inhibit certain cytochrome P450 enzymes, particularly CYP3A4, which are responsible for metabolizing Eliquis and Xarelto in the liver.

As a result, diltiazem slows down the breakdown of Eliquis and Xarelto, leading to elevated levels of these blood thinners in the body. This heightened concentration increases the risk of bleeding complications associated with Eliquis and Xarelto. Therefore, caution is necessary when combining diltiazem with Eliquis or Xarelto.

How Much Does Diltiazem Raise Drug Levels of Eliquis and Xarelto?

Given the p450 enzyme interaction of diltiazem with Eliquis and Xarelto, it slows the breakdown of Eliquis and Xarelto thereby leading to higher drug levels. For example, one study reported that diltiazem increases drug levels of Eliquis by 31% and Xarelto by 40% (I haven’t seen these numbers validated in other studies nor is it clear to me that this is the same reaction for everyone so please take these numbers with “a grain of salt.”)

If you’ve had bleeding issues with these medications, then this drug interaction could be significant. On the other hand, if you’re prone to blood clots, strokes, mini-strokes (TIA), or have a family history of strokes, you and your doctor might be fine with this drug interaction.

What is the Latest Study on Combining Diltiazem with Eliquis or Xarelto?

The research that got my attention involved 204,155 Medicare patients with atrial fibrillation, with a median age of 77 years. Among them, 53,275 individuals were prescribed diltiazem, while 150,880 were using metoprolol to regulate their atrial fibrillation heart rate.

Among those using diltiazem, the risk of hospitalization due to bleeding was found to be 22% higher compared to those using metoprolol for controlling their atrial fibrillation heart rate. Interestingly, for patients on the lowest dose of the extended-release version of diltiazem (120 mg once daily), their risk of bleeding was only 13% higher.

Because patients were not randomized in this study, it’s uncertain if there were underlying factors influencing why one rate-controlling medication was prescribed over another. This lack of randomization could have introduced unintended biases to the study.

For instance, considering the reported higher risk of falls in elderly individuals using beta-blockers like metoprolol, it’s conceivable that physicians may have prescribed diltiazem to patients who were perceived as being more frail. Therefore, the observed increased bleeding risk associated with diltiazem, when combined with Eliquis or Xarelto, might be attributed to factors such as frailty and not the potential drug interaction.

What Do Other Studies Say About Combining Diltiazem with Eliquis or Xarelto?

Given the known cytochrome P450 enzyme interactions when combining medications, a number of studies have looked at the interaction of diltiazem with either Eliquis or Xarelto. Surprisingly, while many studies have called out an increased of bleeding when combining these medications, many have not. For example, in another large study of 91,330 people in Taiwan taking these blood thinners, diltiazem did not increase the risk of bleeding when combined with Eliquis or Xarelto.

Dr. Day’s Take on This Study

Managing drug interactions can be challenging since it seems like almost every medication can interact with something. When it comes to combining diltiazem with Eliquis or Xarelto and the risk of bleeding, it’s still not entirely clear. Some studies suggest there might be a higher risk of bleeding, while others don’t show this. Even the guidelines for treating atrial fibrillation (AFib) don’t give any specific advice on using diltiazem with Eliquis or Xarelto.

In my practice, I haven’t noticed a higher risk of bleeding with diltiazem compared to metoprolol. However, since severe bleeding events with Eliquis and Xarelto are quite rare, I would probably need to see 200,000 or more older patients on these medications, like the number of patients in this study, to see any noticeable differences.

Also, this study included patients with a median age of 77 years. Is this potential bleeding risk of diltiazem, when combined with Eliquis or Xarelto, even significant in younger patients? As of now we still don’t know.

Following the results of this most recent study, I’m discussing alternatives to diltiazem with my AFib patients on these blood thinners. And after these conversations, some are deciding to stick with diltiazem because they’ve done very well without any bleeding issues, while others are switching to different medications. Some are even choosing to steer completely clear of medications altogether and are exploring options such as atrial fibrillation pulsed field ablation or the Watchman procedure.

What Other Medications Can Be Used to Slow the AFib Heart Rate?

For my patients choosing to replace diltiazem with a different medication, most are opting for metoprolol, which is my favorite beta-blocker medication. While metoprolol doesn’t have the same interaction with the p450 enzyme, it does have different side effects to consider. For example, some studies show an increased risk of falls with metoprolol in older patients (other studies refute this), and falls may also increase the risk of bleeding.

Other than calcium channel blockers like diltiazem or beta-blockers like metoprolol, there is only one other medication option for slowing the AFib heart rate, and that is digoxin. While digoxin has been used safely for more than a hundred years, it has lately fallen out of favor due to other non-randomized studies like these which suggest an increased risk of death and hospitalization with this medication. However, it’s important to approach non-randomized studies like these cautiously because they can often be inaccurate in their study findings.

Can You Stay on Diltiazem and Switch to a Different Blood Thinner?

While Eliquis, in my opinion, is the best overall blood thinner to prevent strokes and minimize the risk of bleeding, there are certainly other blood thinners that can be tried so that people can stay on diltiazem. For example, warfarin (also known as Coumadin) doesn’t interact with diltiazem this way. However, warfarin requires a very strict diet and frequent blood tests. Also, unless warfarin is perfectly controlled, it may not be as effective or safe as Eliquis or Xarelto.

Another option is Savaysa (endoxaban), which is in the same factor Xa inhibitor family as Eliquis and Xarelto but has less of a drug interaction with diltiazem. Lastly, Pradaxa (dabigatran) could be tried for people without kidney disease. However, even though Pradaxa is in a different blood thinner family than Eliquis, Xarelto, or Savaysa, one study showed a significant increased risk of bleeding when combining this drug with diltiazem.

What Should You Do?

The key takeaway from this study is that combining diltiazem with Eliquis or Xarelto might increase your risk of bleeding. Therefore, my suggestion would be that if you are on diltiazem with either Eliquis or Xarelto, you schedule an appointment with your prescribing physician to discuss this drug interaction and whether or not it makes sense for you to switch medications or explore other alternatives.

Disclaimer

The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice. It is not a substitute for professional medical guidance or treatment. Always consult with a qualified healthcare provider for diagnosis, treatment, and personalized recommendations regarding your medical condition. Additionally, never stop a medication on your own without first discussing with your prescribing physician.

About the Photo

Captured the vibrant spring bloom in Salt Lake City, with the majestic Mount Olympus providing a breathtaking backdrop. Snapped this moment while strolling down our neighborhood street with my children and our furry companion.