Tag: Clinical

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Clopidogrel monotherapy linked with reduced risk of net adverse clinical events, study finds

Clopidogrel monotherapy linked with reduced risk of net adverse clinical events, study finds

Results from a real-world study investigating safety and effectiveness of clopidogrel versus aspirin monotherapy beyond 12 months after PCI in high-risk patients during the chronic maintenance period. This study found that clopidogrel monotherapy was associated with reduced risk of net adverse clinical events (NACE; all-cause death, MI, stent thrombosis, stroke, or BARC type 2, 3, or 5 bleeding) and MACCE (death, MI, stent thrombosis, stroke), and a numerical decrease in major or clinically relevant nonmajor bleeding (BARC type 2, 3, or 5 bleeding), compared with aspirin monotherapy. The findings were presented today as late-breaking clinical research at the Society for Cardiovascular Angiography & Interventions (SCAI) 2022 Scientific Sessions.

P2Y12 inhibitor monotherapy reduces bleeding risk without increasing the risk of ischemic events compared with dual antiplatelet therapy (DAPT), especially in the first 12 months following percutaneous coronary intervention (PCI). Recent research showed that among patients who were event free for six to 18 months post-PCI and successfully received the intended duration of DAPT, clopidogrel monotherapy was superior compared with aspirin monotherapy in terms of NACE. However, optimal antiplatelet monotherapy during the chronic maintenance period beyond 12 months after PCI with drug-eluting stents in high-risk patients in real-world settings is previously unknown.

In total, 8,377 consecutive patients at high risk for both bleeding and thrombosis were identified from the prospective Fuwai PCI Registry if they satisfied one clinical and one angiographic criterion. Patients who received antiplatelet (aspirin or clopidogrel) monotherapy longer than 12 months and were free from ischemic and bleeding events at 12-month post-PCI without extended duration of DAPT were included. The primary endpoint was net adverse clinical events (NACE) from 12 to 30 months. The key secondary endpoints were major adverse cardiac or cerebral events (MACCE) and major or clinically relevant nonmajor bleeding (BARC type 2, 3 or 5).

“These findings show for the first time clopidogrel monotherapy is associated with reduced risk of long-term NACE and MACCE,” said Hao-Yu Wang, Cardiometabolic Medicine Center, Coronary Heart Disease Center, Department of Cardiology, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. “Our results may have important practical implications for determining the optimal treatment for patients requiring a single antiplatelet drug, either aspirin or clopidogrel, for secondary prevention of ischemic events in high-risk PCI population.”

Of 7,392 high-risk patients that were event-free after the first year and adherent to DAPT, 5,664 patients who received antiplatelet monotherapy (clopidogrel monotherapy: n=1,974 and aspirin monotherapy: n=3690) were included in the present analysis. Researchers found that between 12 and 30 months, the net adverse clinical events were lower with clopidogrel monotherapy compared to aspirin monotherapy (Kaplan-Meier estimate: 2.5% vs. 5.0%; adjusted HR:0.566, 95% CI: 0.403-0.795). Clopidogrel monotherapy was associated with lower risk for MACCE (Kaplan-Meier estimate: 1.0% vs. 3.1%, log-rank p = 0.001 ), as well as lower incidence rates of all-cause death, MI, and stroke. The difference in risk between the groups was statistically similar for major or clinically relevant nonmajor bleeding (Kaplan-Meier estimate: 1.5% vs. 2.1%, log-rank p = 0.199).

Researchers recommended that their findings should be further investigated through a randomized clinical trial.

Source:

Society for Cardiovascular Angiography and Interventions

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Low-Sodium Diet Did Not Cut Clinical Events in Heart Failure

Low-Sodium Diet Did Not Cut Clinical Events in Heart Failure

A low-sodium diet was not associated with a reduction in future clinical events in a new study in ambulatory patients with heart failure. But there was a moderate benefit on quality of life and New York Heart Association (NYHA) functional class.

The results of the SODIUM-HF trial were presented today at the American College of Cardiology (ACC) 2022 Scientific Session, conducted virtually and in-person in Washington, DC. They were also simultaneously published online in The Lancet.

The study found that a strategy to reduce dietary sodium intake to less than 1500 mg daily was not more effective than usual care in reducing the primary endpoint of risk for hospitalization or emergency department visits due to cardiovascular causes or all-cause death at 12 months.

“This is the largest and longest trial to look at the question of reducing dietary sodium in heart failure patients,” lead author, Justin Ezekowitz, MBBCh, from the Canadian VIGOUR Center at the University of Alberta, Edmonton, Canada, told theheart.org |Medscape Cardiology.

But he pointed out that there were fewer events than expected in the study, which was stopped early because of a combination of futility and practical difficulties caused by the COVID pandemic, so it could have been underpowered. Ezekowitz also suggested that a greater reduction in sodium than achieved in this study or a longer follow-up may be required to show an effect on clinical events.

“We hope others will do additional studies of sodium as well as other dietary recommendations as part of a comprehensive diet for heart failure patients,” he commented.

Ezekowitz said that the study results did not allow blanket recommendations to be made on reducing sodium intake in heart failure.

But he added: “I don’t think we should write off sodium reduction in this population. I think we can tell patients that reducing dietary sodium may potentially improve symptoms and quality of life, and I will continue to recommend reducing sodium as part of an overall healthy diet. We don’t want to throw the baby out with the bathwater.”

Ezekowitz noted that heart failure is associated with neurohormonal activation and abnormalities in autonomic control that lead to sodium and water retention; thus, dietary restriction of sodium has been historically endorsed as a mechanism to prevent fluid overload and subsequent clinical outcomes; however, clinical trials so far have shown mixed results.

“The guidelines used to strongly recommend a reduction in sodium intake in heart failure patients, but this advice has backed off in recent years because of the lack of data. Most heart failure guidelines now do not make any recommendations on dietary sodium,” he said.

SODIUM-HF was a pragmatic, multinational, open-label, randomized trial conducted in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand), which included 809 patients (median age, 67 years) with chronic heart failure (NYHA functional class II–III) who were receiving optimally tolerated guideline-directed medical treatment. They were randomly assigned to usual care according to local guidelines or a low-sodium diet of less than 100 mmol (<1500 mg/day). Patients with a baseline sodium intake of less than 1500 mg/day were excluded.

In the intervention group, patients were asked to follow low-sodium menus developed by dietitians localized to each region. They also received behavioral counseling by trained dietitians or physicians or nurses.

Dietary sodium intake was assessed by using a 3-day food record (including 1 weekend day) at baseline, 6 months, and 12 months in both groups and, for the intervention group, also at 3 and 9 months to monitor and support dietary adherence.

Ezekowitz explained that although the best method for measuring sodium levels would normally be a 24-hour urine sodium, this would be impractical in a large clinical trial. In addition, he pointed out that urinary sodium is not an accurate measure of actual sodium levels in patients taking diuretics, so it is not a good measure to use in a heart failure population.

“The food record method of assessing sodium levels has been well validated; I think we measured it as accurately as we could have done,” he added.

Results showed that between baseline and 12 months, the median sodium intake decreased from 2286 mg/day to 1658 mg/day in the low-sodium group and from 2119 mg/day to 2073 mg/day in the usual care group. The median difference between groups was 415 mg/day at 12 months.

By 12 months, events comprising the primary outcome (hospitalization or emergency department visits due to cardiovascular causes or all-cause death) had occurred in 15% of patients in the low-sodium diet group and 17% of those in the usual care group (hazard ratio [HR], 0.89 [95% CI, 0.63 – 1.26]; P = .53).

All-cause death occurred in 6% of patients in the low-sodium diet group and 4% of those in the usual care group (HR, 1.38; P = .32). Cardiovascular-related hospitalization occurred in 10% of the low-sodium group and 12% of the usual care group (HR, 0.82; P = .36), and cardiovascular-related emergency department visits occurred in 4% of both groups (HR, 1.21; P = .60).

The absence of treatment effect for the primary outcome was consistent across most prespecified subgroups, including those with higher vs lower baseline sodium intake. But there was a suggestion of a greater reduction in the primary outcome in individuals younger than age 65 years than in those age 65 years and older.

Quality-of-life measures on the Kansas City Cardiomyopathy Questionnaire (KCCQ) suggested a benefit in the low-sodium group, with mean between-group differences in the change from baseline to 12 months of 3.38 points in the overall summary score, 3.29 points in the clinical summary score, and 3.77 points in the physical limitation score (all differences were statistically significant).

There was no significant difference in 6-minute-walk distance at 12 months between the low-sodium diet group and the usual care group.

NYHA functional class at 12 months differed significantly between groups; the low-sodium diet group had a greater likelihood of improving by one NYHA class than the usual care group (odds ratio, 0.59; P = .0061).

No safety events related to the study treatment were reported in either group.

Ezekowitz said that to investigate whether longer follow-up may show a difference in events, further analyses are planned at 2 years and 5 years.

Questions on Food Recall and Blinding

Commenting on the findings at the late-breaking clinical trials session at the ACC meeting, Biykem Bozkurt, MD, professor of medicine at Baylor College of Medicine, Houston, Texas, congratulated Ezekowitz on conducting this trial.

“We have been chasing the holy grail of sodium reduction in heart failure for a very long time, so I have to commend you and your team for taking on this challenge, especially during the pandemic,” she said.

But Bozkurt questioned whether the intervention group actually had a meaningful sodium reduction given that this was measured by food recall and this may have been accounted for by under-reporting of certain food intakes.

Ezekowitz responded that patients acted as their own controls in that calorie intake, fluid intake, and weight were also assessed and did not change. “So I think we did have a meaningful reduction in sodium,” he said.         

Bozkurt also queried whether the improvements in quality of life and functional status were reliable given that this was an unblinded study.

To this point, Ezekowitz pointed out that the KCCQ quality-of-life measure was a highly validated instrument and that improvements were seen in these measures at 3, 6, and 12 months. “It is not like these were spurious findings, so I think we have to look at this as a real result,” he argued.

Commenting on the study at an ACC press conference, Mary Norine Walsh, MD, director of the heart failure and cardiac transplantation programs at St Vincent Heart Center in Indianapolis, Indiana, said the trial had answered two important questions: that sodium reduction in heart failure may not reduce heart failure hospitalization/death but that patients feel better.

 “I think we can safety tell patients that if they slip up a bit they may not end up in hospital,” she added.

This study was funded by the Canadian Institutes of Health Research and the University Hospital Foundation (Edmonton, Alberta, Canada) and the Health Research Council of New Zealand. Ezekowitz reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, eko.ai, US2.ai, Merck, Novartis, Otsuka, Sanofi, and Servier and consulting fees from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Merck, Novartis, Otsuka, Sanofi, and Servier.

American College of Cardiology (ACC) 2022 Scientific Session. Presented April 2, 2022.

Lancet. Published online April 2, 2022. Abstract

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New Post-Marketing Safety Analysis Shows Rate of Hearing-Related Events Associated with TEPEZZA® (teprotumumab-trbw) Comparable with Clinical Trial Observations

New Post-Marketing Safety Analysis Shows Rate of Hearing-Related Events Associated with TEPEZZA® (teprotumumab-trbw) Comparable with Clinical Trial Observations

DUBLIN–()–Horizon Therapeutics plc (Nasdaq: HZNP) today announced results from a new post-marketing safety analysis of hearing events associated with TEPEZZA for the treatment of Thyroid Eye Disease (TED). These findings, along with data on the sustainability of response to TEPEZZA, were presented at the 48th Annual Meeting of the North American Neuro-Ophthalmology Society (NANOS 2022), Feb. 12-17, in Austin, Texas. TEPEZZA is the first and only medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of TED – a serious, progressive and potentially vision-threatening rare autoimmune disease.1

Since the FDA approval in 2020, Horizon has conducted post-marketing monitoring to understand the overall safety profile of TEPEZZA, including hearing-related events. Among the thousands of patients included in this 19-month analysis (Jan. 2020 – Aug. 2021), approximately 10% of all cases reported to the safety database have included a hearing-related event. The most frequently reported hearing event was hypoacusis (reduction in hearing), followed by tinnitus (ringing in the ears). The mean age of the patient, where known, was 59.3 years. No new safety concerns were observed in the post-marketing database.2

This is comparable with what was seen in the pooled OPTIC Phase 3 and OPTIC-X open-label extension trials for TEPEZZA. Hearing-related adverse events were reported in 9.5% (8/84) of patients treated with TEPEZZA, which were mild or moderate in severity, versus 0% of patients who received placebo. Adverse events experienced in the clinical trials were manageable, with few discontinuations or therapy interruptions.3,4

“The majority of hearing-related adverse events in the pivotal trials and post-approval have been mild to moderate and reversible, but as with any medicine, it is important to monitor patients,” said Kimberly Cockerham, M.D., adjunct clinical associate professor, Department of Ophthalmology, Stanford University School of Medicine, and a primary author of the report. “Notably, we continue to see high patient adherence to TEPEZZA, with more than 90% of patients completing their full course of treatment in the clinical studies and post-approval. This speaks to the favorable benefit-risk profile of TEPEZZA for people living with Thyroid Eye Disease.”

A separate analysis presented at NANOS 2022 examined the sustainability of response to TEPEZZA over the follow-up periods from the Phase 2 and OPTIC Phase 3 clinical trials and the OPTIC-X open-label extension study. A total of 121 patients were analyzed, with 9 patients receiving additional medications and/or surgery during the follow-up periods. Of those with data available, the majority of patients treated with TEPEZZA were proptosis, diplopia and European Group on Graves’ Orbitopathy (EUGOGO) composite outcome responders up to 51 weeks after their last infusion.5

“Managing the disabling symptoms of Thyroid Eye Disease can be difficult for patients, both physically and emotionally, and before TEPEZZA, there was a significant unmet medical need for an effective treatment,” said Jeffrey W. Sherman, M.D., FACP, executive vice president, chief medical officer, Horizon. “Ongoing research reinforces the significant impact TEPEZZA can have on people living with this devastating disease. We are committed to continuing our research to support a positive patient experience with this important medicine.”

About Thyroid Eye Disease (TED)

TED is a serious, progressive and potentially vision-threatening rare autoimmune disease.1 TED often occurs in people living with Graves’ disease, but is a distinct disease that is caused by autoantibodies activating an IGF-1R-mediated signaling complex on cells within the retro-orbital space.6,7 This leads to a cascade of negative effects, which may cause long-term, irreversible damage. TED begins with an acute (active) phase where inflammatory signs and symptoms, such as eye pain, swelling, proptosis (eye bulging) and diplopia (double vision), progress over time.1,8 The disease then enters a chronic phase where inflammation is no longer present or has markedly diminished, but significant signs and symptoms may remain. As TED progresses, the serious damage it can cause includes proptosis (eye bulging), strabismus (misalignment of the eyes) and diplopia (double vision) – and in some cases can lead to blindness.8,9

About TEPEZZA

INDICATION

TEPEZZA is indicated for the treatment of Thyroid Eye Disease.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Infusion Reactions: TEPEZZA may cause infusion reactions. Infusion reactions have been reported in approximately 4% of patients treated with TEPEZZA. Reported infusion reactions have usually been mild or moderate in severity. Signs and symptoms may include transient increases in blood pressure, feeling hot, tachycardia, dyspnea, headache and muscular pain. Infusion reactions may occur during an infusion or within 1.5 hours after an infusion. In patients who experience an infusion reaction, consideration should be given to premedicating with an antihistamine, antipyretic, or corticosteroid and/or administering all subsequent infusions at a slower infusion rate.

Preexisting Inflammatory Bowel Disease: TEPEZZA may cause an exacerbation of preexisting inflammatory bowel disease (IBD). Monitor patients with IBD for flare of disease. If IBD exacerbation is suspected, consider discontinuation of TEPEZZA.

Hyperglycemia: Increased blood glucose or hyperglycemia may occur in patients treated with TEPEZZA. In clinical trials, 10% of patients (two-thirds of whom had preexisting diabetes or impaired glucose tolerance) experienced hyperglycemia. Hyperglycemic events should be managed with medications for glycemic control, if necessary. Monitor patients for elevated blood glucose and symptoms of hyperglycemia while on treatment with TEPEZZA. Patients with preexisting diabetes should be under appropriate glycemic control before receiving TEPEZZA.

Adverse Reactions

The most common adverse reactions (incidence ≥5% and greater than placebo) are muscle spasm, nausea, alopecia, diarrhea, fatigue, hyperglycemia, hearing impairment, dysgeusia, headache, dry skin, and menstrual disorders.

Please see Full Prescribing Information or visit TEPEZZAhcp.com for more information.

About Horizon

Horizon is focused on the discovery, development and commercialization of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. Our pipeline is purposeful: We apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives. For more information on how we go to incredible lengths to impact lives, visit www.horizontherapeutics.com and follow us on Twitter, LinkedIn, Instagram and Facebook.

References

  1. Barrio-Barrio J, et al. Graves’ Ophthalmopathy: VISA versus EUGOGO Classification, Assessment, and Management. Journal of Ophthalmopathy. 2015;2015:249125.
  2. Cockerham, K, et al. Post-Marketing Surveillance of Hearing-related Adverse Events in Patients With TED Treated With Teprotumumab. Poster session presented at: 48th Annual Meeting of the North American Neuro-Ophthalmology Society (NANOS); 2022 Feb. 12-17; Austin, TX.
  3. Smith TJ, et al. Teprotumumab for Thyroid-Associated Ophthalmology. N Engl J Med. 2017;376:1748-1761.
  4. Douglas RS, et al. Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med. 2020;382:341-352.
  5. Subramanian, P, et al. Sustainability of Teprotumumab Efficacy in Thyroid Eye Disease. Paper presented at: 48th Annual Meeting of the North American Neuro-Ophthalmology Society (NANOS); 2022 Feb. 12-17; Austin, TX.
  6. Weightman DR, et al. Autoantibodies to IGF-1 Binding Sites in Thyroid Associated Ophthalmopathy. Autoimmunity. 1993;16(4):251–257.
  7. Pritchard J, et al. Immunoglobulin Activation of T Cell Chemoattractant Expression in Fibroblasts from Patients with Graves’ Disease Is Mediated Through the Insulin-Like Growth Factor 1 Receptor Pathway. J Immunol. 2003;170:6348-6354.
  8. Bartalena L, Kahaly GJ, Baldeschi L, et al. The 2021 European Group on Graves’ Orbitopathy (EUGOGO) Clinical Practice Guidelines for the Medical Management of Graves’ Orbitopathy [published online ahead of print]. Eur J Endocrinol. 2021 Jul 1:EJE-21-0479.R1. doi: 10.1530/EJE-21-0479.
  9. McKeag D, et al. Clinical features of dysthyroid optic neuropathy: a European Group on Graves’ Orbitopathy (EUGOGO) survey. Br J Ophthalmol. 2007;91:455-458.

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Clinical, Economic Burden of Corneal Adverse Events in MM Is Low Compared With Total All-Cause Costs

Clinical, Economic Burden of Corneal Adverse Events in MM Is Low Compared With Total All-Cause Costs

Researchers concluded that incident corneal adverse events in patients with multiple myeloma (MM) carry a low clinical and economic burden compared with total all-cause costs and MM-related per-patient-per-month costs.

Although corneal adverse events (AEs) were observed in about 12% of patients with multiple myeloma (MM) treated with anticancer therapies, the clinical and economic burden of treating corneal AEs was low compared with total all-cause or MM-related per-patient-per-month (PPPM) costs, investigators concluded.

“As the current treatment landscape includes newer treatments, better understanding of these targeted treatments and their level of resource utilization is important. Therefore, further research and real-world evidence are warranted to assess the relationship between corneal AEs and MM treatment and to explore costs associated with specific treatments,” the investigators wrote.

In addition, the real-world retrospective cohort study, published in the Journal of Medical Economics, found that the majority of incident corneal AEs reported were mostly treated in outpatient care centers by ophthalmologists rather than by a hematologist or oncologist.

With increased use of novel anticancer therapies, adverse effects on patients’ eyes have become more common. However, given the novelty of many of these agents, oncologists may not be very familiar with the potential ophthalmologic AEs associated with targeted anticancer therapies. Knowing that AEs can affect patient quality of life and increase economic burden on the health care system, there remains a need to assess the incidence and extent of the burden of managing corneal AEs and related symptoms among patients receiving MM therapies.

The investigators collected information from the IQVIA PharMetrics Plus database, which contains adjudicated health insurance claims data from US commercial insurance plans. The evaluation period lasted between January 1, 2011, and December 31, 2017. Adults with newly diagnosed MM and adults with lymphatic or hematopoietic malignant neoplasm were included in the analysis. The index period, defined as the date that a patient first received a novel MM therapy, was from January 1, 2012, to December 31, 2016.

Within the index period, 2120 patients with MM and 26,923 patients with hematologic malignant neoplasm were identified and enrolled into the MM cohort and the hematology cohort.

Among the MM cohort, 248 (11.7%) patients had at least 1 incident of corneal AEs after initial onset of MM therapy. Also, 7.4% of the hematology cohort experienced at least 1 corneal AE after therapy onset. The most commonly reported corneal AEs in the MM cohort were dry eye (6.1%), keratopathy or keratitis (2.5%), blurred vision or decreased acuity (3.4%), and photophobia (0.2%).

For the patients with MM who reported a corneal AE, the overall median PPPM cost for a corneal AE was $27, representing less than 1% of the median all-cause costs during the follow-up period. The median total all-cause PPPM cost was $17,286 and the median MM-related PPPM cost was $13,851. The investigators noted that the costs were primarily driven by outpatient care, as most of the patients visited an outpatient facility for their AEs.

Emergency department visits, which cost a median PPPM of $66, and hospitalizations, which cost a median PPPM of $16, were rate. Reports for blurred vision and decreased acuity were associated with the highest PPPM cost compared with other corneal AEs, costing a median PPPM of $41.

The use of a 12-month washout period to identify newly treated patients, lack of generalizability to the general MM population or to patients with MM older than 65 years who are enrolled in Medicare, and lack of information on comorbidities were listed as study limitations. Additionally, there may be a potential underreporting of corneal AEs because older patients have a higher risk of dry eye syndrome.

Reference

Wang F, Sansbury L, Ferrante S, et al. Incidence of corneal adverse events in patients with multiple myeloma and their clinical and economic impact: a real-world retrospective cohort study. J Med Econ. 2022:25(1):182-192. doi:10.1080/13696998.2022.2029088