Cardiology Digest podcast: Episode #16

Study #1

First, we discuss the nuanced world of drug interactions involving diltiazem and direct-acting oral anticoagulants like apixaban and rivaroxaban. Tune in as we explore the magnitude of the risk, as well as scrutinize the study's limitations and practical implications for your patients with atrial fibrillation. 

"In a recent study examining Medicare claims data, researchers found that the use of diltiazem was linked to an increased risk of bleeding in patients who were also taking apixaban or rivaroxaban."

Ray, WA, Chung, CP, Stein, CM, et al. 2024. Serious bleeding in patients with atrial fibrillation using diltiazem with apixaban or rivaroxaban. JAMA. 18: 1565–1575. (https://jamanetwork.com/journals/jama/article-abstract/2817546)

Study #2

Next, we turn our attention to a case-control study examining the bleeding risks associated with the combination of selective serotonin reuptake inhibitors and anticoagulants in patients with atrial fibrillation. Are the bleeding risks substantial enough to rethink this combination therapy, or are there scenarios where the benefits outweigh the dangers? We'll leave no stone unturned.

"An expert in the field remarked that this study adds substantial weight to the ongoing concerns regarding bleeding risks in patients on SSRIs in addition to their anticoagulants for atrial fibrillation."

Rahman, AA, Platt, RW, Beradid, S, et al. 2024. Concomitant use of selective serotonin reuptake inhibitors with oral anticoagulants and risk of major bleeding. JAMA. 3: e243208. (https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2816687)

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Study #3

Finally, we’ll explore a fascinating meta analysis that looks at renal denervation and its long-term efficacy in controlling blood pressure. See how renal denervation stacks up against traditional antihypertensive medications and what you need to consider when thinking about incorporating it into your treatment arsenal.

"Renal denervation is an adjunct therapy for treatment-resistant hypertension. Previous studies (usually of patients who were also using antihypertensive medication) showed that renal denervation can lead to a modest decrease in blood pressure."

Sesa-Ashton, G, Nolde, JM, Muente, I, et al. 2024. Long-term blood pressure reductions following catheter-based renal denervation: A systematic review and meta-analysis. Hypertension. 6: e63–e70. (https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.123.22314)

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Please note that these timestamps are auto-generated and may be approximate.

Nora [00:00:06]:

Hello, and welcome to another episode of Medmastery’s Cardiology Digest! I'm your host, Nora, and in less than 15 minutes, I’ll get you up to date on the latest important studies and advancements in cardiology that can impact your clinical practice. Today, we have an exciting lineup of topics. First up, we’ll turn to the pages of JAMA to navigate the complex interactions between diltiazem and direct-acting oral anticoagulants like apixaban and rivaroxaban, and discuss the resulting implications for managing your atrial fibrillation patients. Our next paper, from JAMA Network Open, also involves patients with atrial fibrillation. It’s an interesting case-control study that examined the bleeding risks associated with the combination of selective serotonin reuptake inhibitors and anticoagulants. The big question is whether the risks are significant enough to reconsider this therapy combination, or could there be scenarios where the benefits outweigh the dangers? We’ll explore it all. Lastly, we dive into a meta analysis that looked at renal denervation and its long-term efficacy in controlling blood pressure. We’ll explore how it compares to traditional antihypertensive medications, and what you should consider when thinking of incorporating it into your treatment plans.

Nora [00:01:22]:

Before we get into all that, don’t forget to subscribe so you can stay updated on the latest in cardiology! Now, let's dive right in. In a recent study examining Medicare claims data, researchers found that the use of diltiazem was linked to an increased risk of bleeding in patients who were also taking apixaban or rivaroxaban. The study, titled "Serious bleeding in patients with atrial fibrillation using diltiazem with apixaban or rivaroxaban," was a cohort study conducted by Ray and colleagues. It was published in the Journal of the American Medical Association in April 2024 and fits into a Level 3 category of evidence. Generally, you’ll find stronger evidence near Level 1, and weaker evidence at Level 5, so this paper falls in the middle. Before we go further, here’s a quick review of why this particular combination of medications was of interest in the first place. Patients with atrial fibrillation are susceptible to two critical complications: cardioembolic stroke and rapid ventricular response. 

Nora [00:02:21]:

While therapies for these issues may seem unrelated on the surface, interactions between drugs meant to treat them can complicate matters. Diltiazem is a common rate-control medication that inhibits cytochrome P450 3A4, plus, weakly inhibits P-glycoprotein. So, if a patient taking that medication is also taking a drug that’s metabolized by either of those pathways—such as anticoagulants apixaban or rivaroxaban—blood levels of those drugs can become elevated. Unsurprisingly, there are smaller observational studies which suggest that combining these medications can increase the risk of bleeding. In this new JAMA paper, researchers analyzed data from over 200 000 Medicare beneficiaries with atrial fibrillation who were taking metoprolol or diltiazem, and also taking either apixaban or rivaroxaban. The median follow-up period for these patients was 120 days. For the metoprolol group, there were 50 serious bleeding events per 1000 person-years. But with the calcium channel blocker that increased to 60 events per 1000 person-years, leaving us with a hazard ratio of 1.2.

Nora [00:03:31]:

It’s also important to note that this risk was dose-dependent: higher doses of diltiazem were associated with greater bleeding risk. An expert commenting on the study mentioned 2 potential problems with studies like this one that are based on retrospective claims data: misclassification and residual confounding. However, they still feel these results justify caution regarding the combination of diltiazem with apixaban or rivaroxaban, at least until we have better data to help us better understand the risk. So for now, if possible, it would be wise to consider using a different combination of medications that isn’t known to carry this excess risk of severe bleeding. We’re going to stay on the topic of bleeding risk with this next study, from JAMA Network Open, involving one of the most widely prescribed classes of medication in the world: antidepressants. What did they find? The relative risk of experiencing a major bleeding event was roughly one-third higher for patients taking both anticoagulants and selective serotonin reuptake inhibitors (SSRIs).

Nora [00:04:34]:

The research, titled "Concomitant use of selective serotonin reuptake inhibitors with oral anticoagulants and risk of major bleeding," was a case-control study conducted by Rahman and colleagues. Their findings were published in March of this year, and fit into Level of Evidence Category 4. The investigators used data from over 42 000 patients. The data was sourced from general practices in the UK that contributed to a research database. These patients had atrial fibrillation, were prescribed oral anticoagulants, and then went on to experience a major bleeding event that led to either hospitalization or death. Data from these patients was compared with data from over 1.1 million controls. The mean follow-up period for the study was just under five years. The results—an increased risk of bleeding when these drugs are taken in combination—are in agreement with many previous studies.

Nora [00:05:29]:

The researchers found that the adjusted relative risk of major bleeding jumped by 33% in patients taking both an SSRI and an oral anticoagulant. In absolute numbers, that translates to nine extra major bleeding events per 1000 person-years. This increased risk was consistent for both intracranial and gastrointestinal bleeding, and did not change with the potency of the SSRI. Interestingly, the excess relative risk was 25% when patients were on direct-acting oral anticoagulants. Whereas the excess relative risk was higher—36%—for patients on vitamin K antagonists like warfarin. An expert in the field remarked that this study adds substantial weight to the ongoing concerns regarding bleeding risks in patients on SSRIs in addition to their anticoagulants for atrial fibrillation. This relatively small increase in absolute risk may be acceptable for patients with compelling reasons to be on this combination of medications. But in the absence of strong indications, this additional bleeding risk could be a good reason to avoid mixing SSRIs with oral anticoagulants. 

Nora [00:07:51]:

Our next study is a meta-analysis that showed renal denervation, combined with continued use of multiple antihypertensive medications, brought about lasting reductions in blood pressure. This paper was published in Hypertension in March 2024 by Sesa-Ashton and colleagues. The paper’s level of evidence was rated as 1, which provides a strong level of confidence in these findings. Renal denervation is an adjunct therapy for treatment-resistant hypertension. Previous studies (usually of patients who were also using antihypertensive medication) showed that renal denervation can lead to a modest decrease in blood pressure. But because most of those studies only followed patients in the short-term, more data on the long-term efficacy would be useful. So, this research team sought to provide some clarity.

Nora [00:08:45]:

Their meta analysis pooled results from several studies. It included two randomized controlled trials. These followed 257 renal denervation patients for three years, and compared them to 75 patients who had a sham procedure. The analysis also included four observational studies with an average follow-up period of eight years (these followed 264 patients who received renal denervation). The results were encouraging! Both the observational and randomized controlled trials showed that patients who received renal denervation had clinically significant reductions of blood pressure. Exactly how much of an impact did this have? In the observational studies, the average reduction of systolic blood pressure was 14.8±3.4 mmHg.

Nora [00:09:35]:

And in the randomized controlled trials, the average sham-adjusted reduction of systolic blood pressure was 12.7±4.5 mmHg. The next question that comes to mind is whether or not renal denervation had a negative impact on renal function. The answer is music to our ears: renal denervation did not have a negative impact on renal function. Any declines in renal function were in line with what we’d expect with regular aging. Experts say the data reinforces the view that renal denervation can provide significant, lasting reductions in blood pressure for patients. However, there's a critical point to remember: despite renal denervation’s benefits (especially for patients with treatment-resistant hypertension), the vast majority of patients who undergo renal denervation will still need to continue taking a significant amount of medications to control their blood pressure.

Nora [00:10:28]:

So, consider it to be a potential adjunct therapy for patients with treatment-resistant hypertension, but not a cure. Now let’s make this a two-way conversation. Because I don’t only want to talk to you, I want to talk with you! Sounds good? So, if you have a comment about the research we just went over together, if it reminded you about a clinical encounter you’ve had that’s a story just begging to be told, write to us at support@medmastery.com to share it, and it might be featured in a future episode! Next, don’t forget to subscribe so you never miss an episode! And remember that if you have any feedback about what you heard today, we’d love to hear from you, so please don’t hesitate to email us at support@medmastery.com. New to Medmastery? We offer internationally accredited CME courses via our digital education platform that’s received multiple awards for outstanding digital education. Medmastery is highly commended by the British Medical Association, is trusted by residency programs and universities around the world, and is rated excellent by hundreds of users on Trustpilot.

Nora [00:11:31]:

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