Subcutaneous infusion of high-dose benzathine penicillin G is safe, tolerable, and suitable for less-frequent dosing for rheumatic heart disease secondary prophylaxis: a phase 1 open-label population pharmacokinetic study.

Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order (t1/2 = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng/mL (0.02 µg/mL) was 57 days for 10.8 MU delivered by subcutaneous infusion every 13 weeks compared with 9 days of every 4-weekly dosing interval for the standard 1.2 MU intramuscular dose (i.e., 63% and 32% of the dosing interval, respectively). High-dose SCIP (BPG) is safe, has acceptable tolerability, and may be suitable for up to 3 monthly dosing intervals for secondary prophylaxis of RHD.

Warfarin faring better: vitamin K antagonists beat rivaroxaban and apixaban in the INVICTUS and PROACT Xa trials.

Although guidelines give preference to direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs) for stroke prevention in most patients with atrial fibrillation (AF), DOACs are not recommended in those with rheumatic heart disease or mechanical heart valves. The results of the INVICTUS trial (Investigation of Rheumatic AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies), which compared rivaroxaban with a VKA in patients with rheumatic heart disease-associated AF, and the PROACT Xa trial (A Trial to Determine if Participants with an On-X Aortic Valve Can be Maintained Safely on Apixaban), which compared apixaban with warfarin in patients with an On-X valve in the aortic position, support the use of VKAs for these indications. In this paper, we review the results of these trials, provide perspective on why VKAs were superior to DOACs, and discuss future directions for anticoagulation in these disorders.

The aetiology and incidence of infective endocarditis in people living with rheumatic heart disease in tropical Australia.

PURPOSE: To define the incidence and microbiological aetiology of infective endocarditis (IE) in patients with rheumatic heart disease (RHD) in tropical Australia. METHODS: A retrospective study that examined all episodes of IE between January 1998 and June 2021 among individuals on the RHD register in Far North Queensland, Australia. RESULTS: There were 1135 individuals with a diagnosis of RHD on the register during the study period, representing 10962 patient-years at risk. Overall, there were 18 episodes of definite IE occurring in 16 individuals, although only 7 episodes occurred in native valves (11 occurred in prosthetic valves) equating to 0.7 episodes of native valve IE/1000 patient-years. No patient with mild RHD - and only one child with RHD - developed IE during the study period. Despite the study's tropical location, the causative organism was usually typical skin or oral flora. Among individuals with an indication for benzathine penicillin G (BPG) prophylaxis, only 1/6 episodes of IE due to a penicillin-susceptible organism received BPG in the month before presentation. CONCLUSION: Although RHD predisposes individuals to IE, the absolute risk of IE in native valve disease in tropical Australia is low and might be reduced further by improved adherence to secondary BPG prophylaxis.

Development of a sustained release implant of benzathine penicillin G for secondary prophylaxis of rheumatic heart disease.

BACKGROUND: Regular intramuscular (i.m.) benzathine penicillin G (BPG) injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. Patient adherence to IM BPG is poor, largely due to pain, the need for regular injections every 3-4 weeks and health sector delivery challenges in resource-limited settings. There is an urgent need for new approaches for secondary prophylaxis, such as an implant which could provide sustained penicillin concentrations for more than 6 months. METHODS: In this study we developed and evaluated a slow release implant with potential for substantially extended treatment. The side wall of a solid drug rich core was coated with polycaprolactone which acts as an impermeable barrier. The exposed surfaces at the ends of the implant defined the release surface area, and the in vitro release rate of drug was proportional to the exposed surface area across implants of differing diameter. The in vivo pharmacokinetics and tolerability of the implants were evaluated in a sheep model over 9 weeks after subcutaneous implantation. RESULTS: The absolute release rates obtained for the poorly water-soluble benzathine salt were dependent on the exposed surface area demonstrating the impermeability of the wall of the implant. The implants were well-tolerated after subcutaneous implantation in a sheep model, without adverse effects at the implantation site. Gross structural integrity was maintained over the course of the study, with erosion limited to the dual-exposed ends. Steady release of penicillin G was observed over the 9 weeks and resulted in approximately constant plasma concentrations close to accepted target concentrations. CONCLUSION: In principle, a long acting BPG implant is feasible as an alternative to i.m. injections for secondary prophylaxis of RHD. However, large implant size is currently a significant impediment to clinical utility and acceptability.

Research opportunities for the primordial prevention of rheumatic fever and rheumatic heart disease-streptococcal vaccine development: a national heart, lung and blood institute workshop report.

Streptococcus pyogenes, also known as group A streptococcus (StrepA), is a bacterium that causes a range of human diseases, including pharyngitis, impetigo, invasive infections, and post-infection immune sequelae such as rheumatic fever and rheumatic heart disease. StrepA infections cause some of the highest burden of disease and death in mostly young populations in low-resource settings. Despite decades of effort, there is still no licensed StrepA vaccine, which if developed, could be a cost-effective way to reduce the incidence of disease. Several challenges, including technical and regulatory hurdles, safety concerns and a lack of investment have hindered StrepA vaccine development. Barriers to developing a StrepA vaccine must be overcome in the future by prioritising key areas of research including greater understanding of StrepA immunobiology and autoimmunity risk, better animal models that mimic human disease, expanding the StrepA vaccine pipeline and supporting vaccine clinical trials. The development of a StrepA vaccine is a complex and challenging process that requires significant resources and investment. Given the global burden of StrepA infections and the potential for a vaccine to save lives and livelihoods, StrepA vaccine development is an area of research that deserves considerable support. This report summarises the findings of the Primordial Prevention Working Group-VAX, which was convened in November 2021 by the National Heart, Lung, and Blood Institute. The focus of this report is to identify research gaps within the current StrepA vaccine landscape and find opportunities and develop priorities to promote the rapid and successful advancement of StrepA vaccines.

Adherence to secondary prevention of rheumatic fever and rheumatic heart disease in young people: an 11-year retrospective study.

OBJECTIVES: To evaluate the secondary prevention of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) in the Townsville region, Australia. METHODS: Adherence to benzathine benzylpenicillin G (BPG) was determined for 196 children and young adults aged under 22 years between January 2009 and December 2019, and factors associated with BPG adherence were analysed. Secondary outcomes included attendance at specialist reviews and echocardiograms. RESULTS: Adequate adherence (80%) to regular BPG injections was met by 51.1% of the cohort. Adequate BPG adherence more likely occurred for those that attended the Paediatric Outreach Clinic (OR4.15, 95%CI:2.13-8.05) or a school delivery program (OR1.87, 95%CI:1.11-3.45). People with moderate/severe RHD had greater BPG adherence (OR1.76,95%CI:1.00-3.10). People in rural/remote areas were less likely to have adequate BPG adherence compared to urban counterparts (OR0.31, 95%CI:0.15-0.65). Adherence to echocardiography was 66% and specialist review attendance was 12.5-50%. CONCLUSION: Half of the cohort in the Townsville region received adequate BPG prophylaxis to prevent ARF/RHD. Although rates were relatively higher than those reported in other Australian regions, health delivery goals should be close to 100%. Low attendance at specialist services was reported. Implication for public health: Delivery models with dedicated services, case management and family support could improve BPG adherence in individuals with ARF/RHD. Further resources in rural and remote areas are needed.

Pasteurella Endocarditis in a Patient with Rheumatic Mitral Valve Disease.

BACKGROUND As a common member of the oral bacterial flora of cats and dogs, Pasteurella multocida can cause skin and soft tissue infection in humans after bites, licks, or scratches from animals. Uncommonly, infection due to Pasteurella can cause sepsis in humans. Even more rare is the development of infectious endocarditis from a Pasteurella infection. CASE REPORT A 76-year-old woman presented with malaise and symptoms of fluid overload. Blood cultures were positive for Pasteurella multocida, and an echocardiogram was significant for mitral valve vegetation and severe biatrial enlargement. A diagnosis of Pasteurella endocarditis was made. Surgical intervention was recommended, but owing to the risk involved, the patient elected for conservative management involving long-term treatment with intravenous antibiotics. CONCLUSIONS While exceedingly rare, Pasteurella multocida can cause infectious endocarditis in patients with predisposing factors. This patient had a known history of rheumatic heart disease, which is believed to have caused the significant findings on imaging. To the best of our knowledge, our case is the only one to depict Pasteurella endocarditis in a patient with rheumatic heart disease and severe biatrial enlargement. It is the authors' belief that the rheumatic heart disease and remodeling of the heart increased her susceptibility to severe infection from Pasteurella. The purpose of this case is to describe the pathogenicity of an otherwise low-attack bacterial infection in an elderly patient with underlying structural acquired heart damage.

[Analysis of outcome indexes in randomized controlled trials of traditional Chinese medicine for rheumatic heart disease].

The present study analyzed the efficacy evaluation indexes of the randomized controlled trials(RCTs) of Chinese medi-cine in the treatment of rheumatic heart disease to lay the foundation for the construction of the corresponding core outcome index set. Clinical RCTs with a definite diagnosis of rheumatic heart disease were retrieved from CNKI, Wanfang, VIP, Sino Med, Pub Med, EMbase, and Cochrane Library from January 1, 2010, to December 31, 2020. Thirty-five RCTs were included, involving 3 314 patients and 41 efficacy evaluation indexes, which covered seven domains [traditional Chinese medicine(TCM) symptoms/syndromes, symp-toms/signs, physical and chemical examination, quality of life, long-term prognosis, economic evaluation, and safety events]. Physi-cal and chemical examination(56. 91%) and symptoms/signs(29. 27%) were the more frequently applied. The number of indexes used in a single trial ranged from 1 to 15, with an average of 4. The measurement time points of the top five indexes in the frequency of use were as follows: total response rate was reported at five measurement time points, ranging from 14 days to 6 months; left ventri-cular ejection fraction was measured at eight time points ranging from 5 days to 6 months; left ventricular end systolic diameter was measured at six time points, ranging from 5 days to 6 months; interleukin-2(IL-2) and tumor necrosis factor-α(TNF-α) were repor-ted 28 days after treatment. At present, there are many problems in the efficacy outcome indexes of RCTs in the treatment of rheumatic heart disease with TCM, such as large difference in quantity, unclear primary and secondary indexes, unreasonable selection of " surro-gate indexes", insufficient attention to long-term prognostic indexes and safety event indexes, non-standard application of composite in-dexes, long measurement period, and lack of TCM characteristics. It is urgent to establish the core outcome set for TCM treatment of rheumatic heart disease.

Penicillin Reactions in Patients With Severe Rheumatic Heart Disease: A Presidential Advisory From the American Heart Association.

Secondary antibiotic prophylaxis with regular intramuscular benzathine penicillin G (BPG) is the cornerstone of rheumatic heart disease management. However, there is a growing body of evidence that patients with rheumatic heart disease who have severe valvular heart disease with or without reduced ventricular function may be dying from cardiovascular compromise following BPG injections. This advisory responds to these concerns and is intended to: (1) raise awareness, (2) provide risk stratification, and (3) provide strategies for risk reduction. Based on available evidence and expert opinion, we have divided patients into low- and elevated-risk groups, based on symptoms and the severity of underlying heart disease. Patients with elevated risk include those with severe mitral stenosis, aortic stenosis, and aortic insuffiency; those with decreased left ventricular systolic dysfunction; and those with no symptoms. For these patients, we believe the risk of adverse reaction to BPG, specifically cardiovascular compromise, may outweigh its theoretical benefit. For patients with elevated risk, we newly advise that oral prophylaxis should be strongly considered. In addition, we advocate for a multifaceted strategy for vasovagal risk reduction in all patients with rheumatic heart disease receiving BPG. As current guidelines recommend, all low-risk patients without a history of penicillin allergy or anaphylaxis should continue to be prescribed BPG for secondary antibiotic prophylaxis. We publish this advisory in the hopes of saving lives and avoiding events that can have devastating effects on patient and clinician confidence in BPG.

Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease.

BACKGROUND: Rheumatic heart disease affects more than 40.5 million people worldwide and results in 306,000 deaths annually. Echocardiographic screening detects rheumatic heart disease at an early, latent stage. Whether secondary antibiotic prophylaxis is effective in preventing progression of latent rheumatic heart disease is unknown. METHODS: We conducted a randomized, controlled trial of secondary antibiotic prophylaxis in Ugandan children and adolescents 5 to 17 years of age with latent rheumatic heart disease. Participants were randomly assigned to receive either injections of penicillin G benzathine (also known as benzathine benzylpenicillin) every 4 weeks for 2 years or no prophylaxis. All the participants underwent echocardiography at baseline and at 2 years after randomization. Changes from baseline were adjudicated by a panel whose members were unaware of the trial-group assignments. The primary outcome was echocardiographic progression of latent rheumatic heart disease at 2 years. RESULTS: Among 102,200 children and adolescents who had screening echocardiograms, 3327 were initially assessed as having latent rheumatic heart disease, and 926 of the 3327 subsequently received a definitive diagnosis on the basis of confirmatory echocardiography and were determined to be eligible for the trial. Consent or assent for participation was provided for 916 persons, and all underwent randomization; 818 participants were included in the modified intention-to-treat analysis, and 799 (97.7%) completed the trial. A total of 3 participants (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, as compared with 33 (8.2%) in the control group (risk difference, -7.5 percentage points; 95% confidence interval, -10.2 to -4.7; P<0.001). Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis). CONCLUSIONS: Among children and adolescents 5 to 17 years of age with latent rheumatic heart disease, secondary antibiotic prophylaxis reduced the risk of disease progression at 2 years. Further research is needed before the implementation of population-level screening can be recommended. (Funded by the Thrasher Research Fund and others; GOAL ClinicalTrials.gov number, NCT03346525.).

Analysis of outcome indexes in randomized controlled trials of traditional Chinese medicine for rheumatic heart disease / 中国中药杂志

The present study analyzed the efficacy evaluation indexes of the randomized controlled trials(RCTs) of Chinese medi-cine in the treatment of rheumatic heart disease to lay the foundation for the construction of the corresponding core outcome index set. Clinical RCTs with a definite diagnosis of rheumatic heart disease were retrieved from CNKI, Wanfang, VIP, Sino Med, Pub Med, EMbase, and Cochrane Library from January 1, 2010, to December 31, 2020. Thirty-five RCTs were included, involving 3 314 patients and 41 efficacy evaluation indexes, which covered seven domains [traditional Chinese medicine(TCM) symptoms/syndromes, symp-toms/signs, physical and chemical examination, quality of life, long-term prognosis, economic evaluation, and safety events]. Physi-cal and chemical examination(56. 91%) and symptoms/signs(29. 27%) were the more frequently applied. The number of indexes used in a single trial ranged from 1 to 15, with an average of 4. The measurement time points of the top five indexes in the frequency of use were as follows: total response rate was reported at five measurement time points, ranging from 14 days to 6 months; left ventri-cular ejection fraction was measured at eight time points ranging from 5 days to 6 months; left ventricular end systolic diameter was measured at six time points, ranging from 5 days to 6 months; interleukin-2(IL-2) and tumor necrosis factor-α(TNF-α) were repor-ted 28 days after treatment. At present, there are many problems in the efficacy outcome indexes of RCTs in the treatment of rheumatic heart disease with TCM, such as large difference in quantity, unclear primary and secondary indexes, unreasonable selection of " surro-gate indexes", insufficient attention to long-term prognostic indexes and safety event indexes, non-standard application of composite in-dexes, long measurement period, and lack of TCM characteristics. It is urgent to establish the core outcome set for TCM treatment of rheumatic heart disease.

Impact of renin-angiotensin system inhibitors on long-term clinical outcomes of patients with rheumatic heart disease.

AIMS: Rheumatic heart disease (RHD) remains a major global health problem. Renin-angiotensin-aldosterone system inhibitors (RAASi) are commonly administered in the treatment of cardiovascular disease, but its role in RHD patients is still limited. We performed a retrospective study to determine the effect of RAASi on long-term outcomes for RHD patients. METHODS AND RESULTS: A 1:1 propensity score matching was implemented to balance baseline characteristics between groups RAASi and non-RAASi. Cox proportional hazards regression model was used to investigate the associations of RAASi with the risks of all-cause mortality, cardiovascular death (CVD), and cerebrovascular death. Binary logistic regression analysis was used to evaluate the associations of RAASi with the risks of 1, 3, and 5 year heart failure (HF) rehospitalization, new-onset atrial fibrillation (AF), and new-onset stroke. A total of 734 RHD patients were enrolled as study participants; nearly half of these participants had combined valve damage (54.4%), worse New York Heart Association functional class status (III and IV, 55.2%), surgical treatment (54.2%), and AF (65.0%). After propensity score matching, 514 RHD patients were finally analysed. RAASi treatment was associated with decreased risks of all-cause mortality [adjusted hazard ratio (HR) = 0.52, 95% confidence interval (CI): 0.37-0.73, P < 0.001], CVD (adjusted HR = 0.48, 95% CI: 0.30-0.76, P = 0.002), and cerebrovascular death (adjusted HR = 0.22, 95% CI: 0.08-0.60, P = 0.003). Further subgroup analysis showed that RAASi treatment was associated with decreased risks of all-cause mortality (adjusted HR = 0.50, 95% CI: 0.31-0.79, P = 0.004), CVD (adjusted HR = 0.48, 95% CI: 0.25-0.91, P = 0.025), and cerebrovascular death (adjusted HR = 0.19, 95% CI: 0.05-0.65, P = 0.008) in RHD patients without surgical treatment, and better effect was observed in RHD patients with surgical treatment on the risks of all-cause mortality (adjusted HR = 0.47, 95% CI: 0.26-0.85, P = 0.012) and CVD (adjusted HR = 0.43, 95% CI: 0.21-0.90, P = 0.024) except cerebrovascular death (adjusted HR = 0.52, 95% CI: 0.08-3.36, P = 0.491). RAASi treatment was associated with decreased HF rehospitalization risk of 1 year [adjusted odds ratio (OR) = 0.38, 95% CI: 0.23-0.61, P < 0.001], 3 year (adjusted OR = 0.43, 95% CI: 0.28-0.68, P < 0.001), and 5 year (adjusted OR = 0.48, 95% CI: 0.30-0.77, P = 0.002) as well as new-onset AF risk (adjusted OR = 0.38, 95% CI: 0.21-0.68, P = 0.001). RAASi treatment had nothing to do with new-onset stroke risk (adjusted OR = 0.80, 95% CI: 0.47-1.38, P = 0.428). CONCLUSION: Renin-angiotensin-aldosterone system inhibitor treatment was significantly associated with decreased risks of mortality, HF rehospitalization, and new-onset AF in RHD patients in median 5.9 year follow-up.

Examining the Ugandan health system's readiness to deliver rheumatic heart disease-related services.

BACKGROUND: In 2018, the World Health Assembly mandated Member States to take action on rheumatic heart disease (RHD), which persists in countries with weak health systems. We conducted an assessment of the current state of RHD-related healthcare in Uganda. METHODOLOGY/PRINCIPAL FINDINGS: This was a mixed-methods, deductive simultaneous design study conducted in four districts of Uganda. Using census sampling, we surveyed health facilities in each district using an RHD survey instrument that was modeled after the WHO SARA tool. We interviewed health workers with experience managing RHD, purposively sampling to ensure a range of qualification and geographic variation. Our final sample included 402 facilities and 36 health workers. We found major gaps in knowledge of clinical guidelines and availability of diagnostic tests. Antibiotics used in RHD prevention were widely available, but cardiovascular medications were scarce. Higher levels of service readiness were found among facilities in the western region (Mbarara district) and private facilities. Level III health centers were the most prepared for delivering secondary prevention. Health worker interviews revealed that limited awareness of RHD at the district level, lack of diagnostic tests and case management registries, and absence of clearly articulated RHD policies and budget prioritization were the main barriers to providing RHD-related healthcare. CONCLUSIONS/SIGNIFICANCE: Uganda's readiness to implement the World Health Assembly RHD Resolution is low. The forthcoming national RHD strategy must focus on decentralizing RHD diagnosis and prevention to the district level, emphasizing specialized training of the primary healthcare workforce and strengthening supply chains of diagnostics and essential medicines.

Temporal trends of atrial fibrillation and/or rheumatic heart disease-related ischemic stroke, and anticoagulant use in Chinese population: An 8-year study.

BACKGROUND AND PURPOSE: Underuse of anticoagulants in ischemic stroke patients with atrial fibrillation (AF) and/or rheumatic heart disease (RHD) is a global concern, especially in China. However, the extent to which anticoagulants are underused in AF and/or RHD-related ischemic stroke in China has not been well characterized. We aimed to explore the temporal trends of AF and/or RHD-related ischemic stroke patients, anticoagulation use and factors related to suboptimal use of anticoagulants in a Chinese population. METHODS: Acute ischemic stroke patients admitted to department of neurology, West China hospital, Sichuan university were included from January 1st 2010 to December 31st 2017. Temporal trends of AF and RHD related ischemic strokes were compared over 2 year epochs (2010-2011, 2012-2013, 2014-2015 and 2016-2017). Multivariable logistic regression models were performed to evaluate the variables associated with non-anticoagulants at discharge. RESULTS: Of 4357 acute ischemic stroke patients (≤7 days after onset) included between 2010 and 2017, 823(18.9%) were AF and/or RHD-related. Over the 8 years, the proportion of RHD-ischemic stroke decreased significantly from 7.8% in 2010-2011 to 4.5% in 2016-2017, whereas no reduction in AF-ischemic stroke was observed. There was an increase in the proportion of AF and/or RHD patients who were prescribed anticoagulants at discharge (from 26.4% to 45.1%, P for trend<0.001), while the proportion given antiplatelet therapy decreased with time (from 56.0% to 30.0%, P for trend<0.001). The use of non-vitamin K antagonist oral anticoagulants (NOAC) use at discharge remained low during the study period (2.1%).Older age (per 5 years increase, OR 1.91, 95% CI 1.28-2.86), higher NIHSS score on admission(OR 1.08, 95% CI 1.05-1.11), the presence of non-symptomatic hemorrhagic transformation(OR 2.54, 95% CI 1.67-3.94) and symptomatic hemorrhagic transformation(OR 3.04, 95% CI 1.14-9.73) were independently associated with non-anticoagulant use at discharge. However, patients with a prior diagnosis of AF/RHD and anticoagulation before admission were more likely to receive anticoagulants at discharge. CONCLUSIONS: In an ischemic stroke population in China we found an increasing but still low use of anticoagulation. Further research is required on how to improve anticoagulation use at discharge in ischemic stroke patients, including access to NOAC's.