Archive for month: July, 2024

A recent research published in the European Heart Journal unveiled promising evidence that lipid-lowering therapies (LLT) may significantly reduce the risk of venous thromboembolism (VTE). These LLTs are the high-intensity statins and their combination with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i).

Venous thromboembolism encompasses both deep vein thrombosis and pulmonary embolism and is a major health concern that can lead to severe complications and even death. Statins are widely known for their cholesterol-lowering effects and cardiovascular benefits and is now suggested to also lower the risk of VTE. 

The research team conducted a comprehensive review of randomized controlled trials (RCTs) that involved different LLTs, including statins (both high- and low-/moderate-intensity), ezetimibe, and PCSK9 inhibitors. The study utilized PubMed, CENTRAL and Web of Science databases to source data and encompassed studies up until November 2, 2022. The meta-analysis incorporated data from 45 RCTs, which included a total of 254,933 patients and reported 2,084 VTE events. An additive component network meta-analysis was used to assess and compare the risk of VTE during long-term follow-up across different combinations of LLT.

The results of this study revealed that the combination of PCSK9 inhibitors with high-intensity statins yielded the most significant reduction in VTE risk, with a risk ratio (RR) of 0.59 (95% confidence interval [CI]: 0.43–0.80) when compared to a placebo. This indicates a 41% reduction in VTE risk with this combination therapy.

In terms of monotherapy, the high-intensity statins showed a trend towards reducing VTE risk (RR 0.84; 95% CI: 0.70–1.02), while low-/moderate-intensity statins also indicated a potential reduction (RR 0.89; 95% CI: 0.79–1.00). On the other hand, ezetimibe monotherapy did not demonstrate a significant effect on VTE risk (RR 1.04; 95% CI: 0.83–1.30).

This study highlighted a gradational benefit with increasing intensity of LLT by suggesting that higher doses or more potent therapies might offer greater protection against VTE. Also, the combination of PCSK9 inhibitors with high-intensity statins was significantly more effective in reducing VTE risk than low-/moderate-intensity statin monotherapy (RR 0.66; 95% CI: 0.49–0.89).

This extensive meta-analysis illuminates the potential of LLTs in higher intensity and combination therapies to prevent VTE. The findings advocate for further investigation and clinical studies of these therapies for VTE prevention and managing patients at risk of thromboembolic events.

Source:

Farmakis, I. T., Christodoulou, K. C., Hobohm, L., Konstantinides, S. V., & Valerio, L. (2024). Lipid lowering for prevention of venous thromboembolism: a network meta-analysis. In European Heart Journal. Oxford University Press (OUP). https://doi.org/10.1093/eurheartj/ehae361

Percutaneous Needle Aponeurotomy in Dupuytren’s Contracture: the technique

Dupuytren’s contracture (DC) is a progressive fibroproliferative disorder of an unknown origin affecting palmar fascia, causing irreversible finger flexion contractures. The metacarpophalangeal (MCP) and proximal interphalangeal joints (PIPJs) are the most affected. Contractures can cause hand deformities and poor hand function, resulting in lower quality of life.

Numerous treatments for symptomatic contractures have been proposed. Physical therapy, steroid injection, radiation, 5 fluorouracil injection, and oral tamoxifen are conservative treatments.

Surgical treatment of dupuytren’s disease includes open fasciotomy, partial fasciectomy, radical fasciectomy, dermofasciectomy and percutaneous needle aponeurotomy (PNA). Percutaneous needle fasciotomy has gained popularity in the past three decades which has many potential advantages over open surgery. Nerve injuries are avoided with wide local anesthesia as distal sensibility monitoring is possible during the procedure. The chance of tendon injuries is minimized by monitoring active finger motion. Patients can use their hands and return to work earlier.

The technique by Navaneeth et al:

The procedure of needle aponeurotomy was performed using wide awake local anesthesia with no tourniquet, with an 18 G needle. The cord was palpated by applying pressure and marked using a skin marker.The needle was meticulously inserted in a parallel manner to the skin, with the bevel oriented upward into the cords. Applying stress to the cord moved the needle in both upper and downward directions to sever the cords. Precautions were taken to prevent neurovascular bundles and flexor tendon injury. As the procedure was performed under local anesthesia, any intraoperative injury to the digital nerve could be identified by the tactile withdrawal of the patient. Additional punctures were administered in the same manner along the cord. Following its release, the finger was immobilized in extension using splints. Active mobilization was initiated on first post operative day with an 8 week night splint.

PNA can serve as a major modality for treating Dupuytren contracture or as a means to postpone fasciectomy. Patient results and satisfaction rates are comparable to those of collagenase injection. The recurrence rate is higher as compared to open fasciectomy, especially for younger patients (under 35 years old) and for contractures in the PIPJ. It is cost effective compared to open fasciectomy and collagenase injections. However, it has a steep learning curve, moderate recurrence rate, and faster time to recurrence for PIPJ contracture, with complications including digital nerve injury, neuropraxia, hematoma, skin tears, flexor tendon injury, infections, and recurrence.

Further reading:

Percutaneous needle aponeurotomy in Dupuytren’s contracture.

Navaneeth PK, Bhat AK, Pai GM, Acharya AM.

J Orthop Trauma Reconstr 2024;1:10-3.

DOI: 10.4103/OTR.OTR_9_24

Targeted blood tests, asking patients about risk factors, and dose modifications can lessen the risk of potentially fatal reactions to antiseizure medications that millions of Americans take for epilepsy and other conditions. However, skin reactions in newly medicated patients still require speedy medical attention, according to research from Rutgers Health.

Rashes are a common side effect of antiseizure medications, occurring in 2 to 16 percent of patients and vary by specific drug.

Although most rashes are not life-threatening, roughly 5 percent indicate life-threatening reactions. The FDA recently issued a warning about serious reactions to two antiseizure medications: levetiracetam and clobazam.

“Dangerous reactions are rare, but patients and caregivers should understand the risk and how to respond if side effects occur,” said Ram Mani, chief of the adult epilepsy division at Rutgers Robert Wood Johnson Medical School and lead author of the study published in Current Treatment Options in Neurology.

“Patients should seek medical treatment if rashes develop rather than waiting for them to disappear,” added co-author Cindy Wassef, an assistant professor of dermatology at Robert Wood Johnson Medical School. “If symptoms are mild, they can contact their neurologist or primary care physician, but serious symptoms like a high fever, skin pain, or blisters warrant a trip to the emergency room or a 911 call.”

Despite these risks, antiseizure medicines are important for many medical conditions. The proper antiseizure medication can stop further seizures in 70 percent of patients. Such medications also help many patients with bipolar disorder, anxiety, migraines and neuropathic pain.

This new review synthesizes published data on individual antiseizure medications and distinguishes the different rashes and their triggers.

Risk factors for severe reactions include the use of aromatic antiseizure medications, rapid dose escalation, genetic predisposition, and certain drug interactions.

“Patients who react to one medication are more likely to react to others with structural similarities, but with 30 FDA-approved options, we can typically find each patient an effective treatment with minimal to no side effects,” Mani said.

The most common non-disabling reaction is a rash that typically occurs within two weeks of treatment. It typically affects the torso or limbs with a flat rash or hive-like bumps. It usually disappears without treatment a few weeks after patients stop the medication.

Severe conditions, on the other hand, often require urgent treatment. In Stevens-Johnson syndrome or toxic epidermal necrolysis-which produces fever, eye pain and detached skin-inpatient care is often needed.

Mani estimated that several thousand patients suffer severe reactions to antiseizure medications each year, but the numbers could decrease if neurologists consistently put high-risk patients on low-risk medicines.

“I gave a talk on this topic at the American Epilepsy Society Conference last year, and I asked the more than 200 doctors in the room how frequently they perform the recommended HLA screening tests on indicated patients, and only a handful raised their hands,” Mani said. “So there’s definitely room for improvement to increase patient safety.”

Reference:

Mani, R., Almelegy, A., Truong, T.M. et al. Distinguishing Benign Rashes From Severe Skin Reactions From Anti-Seizure Medications. Curr Treat Options Neurol 26, 115–138 (2024). https://doi.org/10.1007/s11940-024-00785-8.

A new tablet form of ketamine has shown promise in treating severe depression, offering a potential alternative to existing clinic-based treatments that can be expensive and lacking in convenience for some patients.

Unlike the injectable and nasal spray alternatives that require clinicians to monitor patients for two hours while side effects subside, the slow-release tablet form can be taken safely at home without medical supervision and with negligible side effects.

Led by Professor Paul Glue of University of Otago, researchers from UNSW Sydney and the affiliated Black Dog Institute (BDI) collaborated with colleagues from other research institutions in Australia and New Zealand to run a randomised-controlled trial testing the effectiveness of ketamine tablets to treat depression compared with placebo.

The researchers randomly assigned 168 patients with treatment-resistant depression to one of five groups: four that received different strengths of ketamine, and one that received placebo.

Patients on the strongest dose of ketamine-at 180mg, taken orally twice a week-had the best results when compared to placebo, the researchers found. Success was measured by the size of reduction in a patient’s MADRS score-a measure of depression symptoms, where the higher the score, the more serious the depression.

In the 180mg group, the average reduction in MADRS score dropped by 14 points from a high of 30. In the placebo group, the average reduction was 8 points. All of the remaining doses of ketamine (120mg, 60mg and 30mg) had slightly better outcomes than placebo.

The results were published today in Nature Medicine.

Fascinating results

Professor Colleen Loo, who is clinical psychiatrist and researcher with UNSW and BDI, has previously contributed to research on the injectable and nasal spray versions of ketamine treatment for depression.

“The kind of results we’re seeing look as good as other ways of giving ketamine, and are fascinating for two reasons,” she says.

“First of all, there’s the practical clinical reason that this is a way of administering ketamine to treat depression that’s much easier to give. Rather than having to come to the clinic and have an injection and have medical monitoring for two hours, once or twice a week, this is much more convenient and allows patients to have their treatment at home, making it as convenient as other antidepressant medications.

“It is also possible that some people may respond to one approach to treatment, such as the tablet, while others respond to another, such as the injection, so having more treatment approaches is very useful.”

The second reason is that it challenges some beliefs about how ketamine works in helping people successfully overcome depression.

“There’s one school of thought that says what we call dissociative effects – where you’re feeling a kind of altered reality and perception – are actually integral to the ability to improve the depression with ketamine,” Prof. Loo says.

“And that’s very similar to the psychedelic assisted therapy model that says changing your brain circuit functioning in that very profound way gives you new insights that help you to break out of your way of thinking, and that this acute kind of dissociative altered reality experience is necessary for you to improve.

“But with this tablet form you don’t experience that because only a tiny amount is released into the bloodstream at a time, with ongoing slow release over days, and you don’t experience the dissociation at all, and yet people are improving.

“So it could be that the theory that you must have these altered reality perceptions to improve may not be correct.”

Further research needed

The double-blind trial – where the allotment of ketamine or placebo to each group was hidden from both trial administrators and participants – was the first to measure the effectiveness of a slow-release tablet form of ketamine to treat depression. But it is likely years away, and more millions of dollars spent on further trials before it becomes an approved clinical treatment.

“Douglas Pharmaceuticals, which is the New Zealand company that has produced the drug, still needs to do further studies, and it’s important to note this is not yet approved by the FDA in the US or the TGA here in Australia.

“But if it does get through all those hoops and becomes an approved treatment, it certainly makes it much more convenient, not to mention cheaper, to use ketamine to treat severe depression.”

The next step, says Prof. Loo, is for the group to run similar studies in multiple sites around the world in larger numbers of patients to show that the results are reproducible. One such study could look at how the tablet form of ketamine compares with other modes of delivery such as injection, which to date has shown strong results.

Reference:

Glue, P., Loo, C., Fam, J. et al. Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03063-x.

USA: Recent research examining the safety of COVID-19 vaccination during the first trimester of pregnancy has provided reassuring findings regarding the absence of association with major structural birth defects among live births. The study, published in JAMA Pediatrics, addressed concerns and clarified the potential risks of early pregnancy vaccination.