Poor long-term adherence to secondary penicillin prophylaxis in children with history of rheumatic fever

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Poor Long-Term Adherence to Secondary Penicillin Prophylaxis in Children with History of Rheumatic Fever Gil Amarilyo MD , Gabriel Chodick PhD , Jonathan Zalcman MD , Gideon Koren MD , Yoel Levinsky MD , Ido Somekh MD , Liora Harel MD PII: DOI: Reference:

S0049-0172(18)30422-0 https://doi.org/10.1016/j.semarthrit.2018.10.015 YSARH 51411

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Seminars in Arthritis & Rheumatism

Please cite this article as: Gil Amarilyo MD , Gabriel Chodick PhD , Jonathan Zalcman MD , Gideon Koren MD , Yoel Levinsky MD , Ido Somekh MD , Liora Harel MD , Poor Long-Term Adherence to Secondary Penicillin Prophylaxis in Children with History of Rheumatic Fever, Seminars in Arthritis & Rheumatism (2018), doi: https://doi.org/10.1016/j.semarthrit.2018.10.015

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Poor Long-Term Adherence to Secondary Penicillin Prophylaxis in Children with History of Rheumatic Fever Gil Amarilyo1,2, MD, Gabriel Chodick2,3, PhD, Jonathan Zalcman2, MD, Gideon Koren2,3, MD, Yoel Levinsky1,2, MD, Ido Somekh1, MD, Liora Harel1,2, MD

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Affiliations: 1Pediatric Rheumatology Unit, Schneider Children's Medical Center of Israel, Petach Tikva; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; 3 Maccabi Healthcare Services, Medical Informatics, Maccabi Healthcare Services, Tel Aviv, Israel

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Address correspondence to: Liora Harel, Pediatric Rheumatology Unit, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel [[email protected]], +972-3-925-3693

Key Words: Rheumatic Fever, Rheumatic Heart Disease, Adherence, Secondary Prophylaxis

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Conflict of Interest: The authors have no conflicts of interest to disclose.

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Abstract Objective: Recurrent episodes of acute rheumatic fever may contribute to the development or worsening of rheumatic heart disease. Secondary penicillin prophylaxis (SPP) has been found to significantly reduce the incidence of rheumatic heart disease. This study sought to evaluate adherence to oral and intramuscular SPP in pediatric patients with rheumatic fever using real-world data spanning 10 years.

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Methods: The study population included patients <18 years old insured by a 2.1-

million-member health maintenance organization in Israel who were diagnosed with acute rheumatic fever between 1/1996 and 5/2015 and had purchased at least one

monthly dose of oral or intramuscular penicillin by prescription. The mean proportion of days covered by SPP was calculated. The endpoint of the retrospective follow-up

age 18 years, or end of follow-up.

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for therapy discontinuation was leaving the health maintenance organization, death,

Results: The cohort included 842 children: 734 treated with oral penicillin and 108 with intramuscular penicillin. The respective mean (SD) ages of the two groups at diagnosis were 8.6 (3.7) years and 10.9 (3.2) years, and the median (interquartile

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range) proportions of days covered by SPP were 8% (2%-33%) and 10% (3%-28%). Overall, the number of days covered decreased exponentially from 103 days in the

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first year of therapy to 20 days in the tenth year of follow-up. Conclusion: Adherence to SPP for rheumatic fever is poor. This renders this mode of

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long term prophylaxis futile. Although the IM route has been previously shown to be

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more effective, the oral route was more extensively used.

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Introduction

Rheumatic heart disease is a serious complication of acute rheumatic fever. Despite the recent decrease in the incidence and prevalence of acute rheumatic fever in developed nations, rheumatic heart disease remains the second most common

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acquired pediatric heart disease worldwide in developed countries and the first most common in developing countries.1,2,3 Risk factors include living in a developing country, in a crowded environment, and poverty.2 In Australia, for example,

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rheumatic fever is much more common in the minority indigenous population than in the general population.4 Prior to the introduction of penicillin, 50-70% of patients with rheumatic fever had recurrent infections with group A Streptococcus (GAS) followed by a flare of the acute disease and the development or exacerbation of

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rheumatic heart disease.5 The American Heart Association recommends that patients

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with a history of acute rheumatic fever should receive secondary penicillin prophylaxis (SPP) or its equivalent, either oral daily penicillin (penicillin V) or

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monthly intramuscular (IM) penicillin (benzathine penicillin G).6 The IM route has been shown in various studies to be more effective in preventing exacerbations of the

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disease presumably due to better adherence.7-8 Observational and retrospective studies have reported relatively low adherence

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to SPP in patients with rheumatic fever at rates of 45-65%.9,10 However, they had several methodological drawbacks: the evaluations were limited to IM prophylaxis because adherence was measured according to attendance in a health care facility; only small patient samples were included; and the follow-up time was relatively short. The present study sought to address these problems and avoid potential recall bias by

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evaluating adherence to either oral or IM SPP in a large pediatric population using long-term real-life data derived from electronic medical records.

Patients and Methods Patients and setting

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A retrospective cohort study design was used. The study was conducted in Maccabi

Healthcare Services (MHS), a 2.1-million-member health maintenance organization operating in Israel. The central database of MHS was reviewed for all patients up to age 18 years assigned at least one diagnostic code of rheumatic fever (code 390,

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391.0, or 391.9; International Classification of Diseases, 9th revision) between

January 1996 and May 2015. Those who filled at least one prescription of IM SPP (1 monthly dose of benzathine penicillin G) or of oral SPP (at least 28 daily doses of

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penicillin V, potassium, and amoxicillin with or without calvulanic acid) or alternatives (for penicillin-sensitive patients: oral sulfadiazine, macrolides, azalides)

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were identified. The date the first SPP was dispensed was defined as the index date.

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Aviv.

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The study was approved by the Assuta Hospital's Research Ethics Committee in Tel

Study variables and outcomes

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Demographic data at the index date were extracted from the medical files. Treatment persistence was defined as continuation of drug use for the entire duration of therapy or until age 18 years, whichever occurred first. The cutoff for data collection was 18 years because at this age almost all individuals (both males and females) are recruited for mandatory military service and removed from the MHS database. Discontinuation of SPP was defined as the point at which a patient would have had an insufficient

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supply of drug to cover 80% of follow-up days plus a fixed grace period of 30 days.11 Adherence to treatment refers to the extent of drug dispensed during the period of persistence, expressed as mean proportion of days covered (PDC). This was calculated by dividing the quantity of the drug dispensed by the total interval from the index date to age 18 years, leaving the MHS, or April 31, 2015, whichever occurred

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first. The maximum duration of follow-up per patient was approximately 10 years. On the basis of earlier publications on standards of adherence to therapy, we defined a

PDC of >80% as high adherence, 20% to 80% as medium adherence, and <20% as poor adherence.12,13

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In addition, we collected data on follow-up visits to pediatric rheumatology clinics for each patient if applicable and results of GAS cultures performed during the duration of the study.

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Statistical analysis

Chi-square test for categorical variables and Kruskal–Wallis test for continuous

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variables were performed to determine significant differences among groups in

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baseline characteristics and PDC levels. To rule out a potential prevalence/incidence bias, we excluded patients with less than 1 year of follow-up. In addition, we

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conducted sensitivity analyses limited to patients with at least 5 years of follow-up. Tests for trends of ordinal variables were based on the category median values. Chi-

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square test was performed to assess heterogeneity. For comparison of patients with positive and negative GAS cultures, the non-parametric Wilcoxon's matched pairs test was used.

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Results A total of 842 children met the inclusion criteria: 734 were prescribed oral SPP and 108, IM SPP. Mean (SD) ages at diagnosis (initial therapy) of the two groups were 8.6 (3.7) years and 10.9 (3.2) years, respectively. Overall, 83% of the cohort was

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followed for 5 years or more and 39% for the entire 10 year period. The regimens

used for secondary prophylaxis are listed in Table 1. All patients in the IM SPP group were treated with benzathine penicillin G. Patients in the oral SPP group received

mainly penicillin VK (57.6%) and amoxicillin (30.4%); the remainder received non-

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penicillin regimens (11.9% macrolides and 0.1% sulfadiazine) presumably because of penicillin allergy. The rates of presumed penicillin allergy are comparable to the

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reported literature.14

For the whole cohort, in the first year of therapy, 102.9 out of 365 days (28.2%) were

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covered by SPP. The PDC was significantly higher in the oral SPP group than in the

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IM SPP group (107.3 days, 29.3% vs. 72.6 days, 19.9%; P ≤0.005). There was an exponential decrease in SPP coverage from the first year to the tenth year (20.8 days,

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5.7%; Figure 1A-C). No significant difference in in PDC was noted between the oral and IM SPP groups in any year throughout follow-up except for the first (Figure 1D).

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The median (interquartile range, IQR) PDC values for the treatment regimens over the total period were 8% (2-33%) for oral SPP and 10% (3-28%) for IM SPP. We also examined whether a visit to a pediatric rheumatology clinic increased adherence to SPP (Table 2). Overall, 3 months before a clinic visit, 45.7% of patients had good adherence, and 3 months after, the rate increased to 61.2%. There was a trend towards

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significance for the whole cohort (P ≤0.06), but division into oral and IM SPP groups yielded nonsignificant results.

A total of 547 GAS cultures were taken during the study period (Table 3) of which 54 (10%) were positive. In the oral SPP group, 3 of the 49 patients (6%) with positive

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cultures had good adherence compared to 187 of the 371 patients (50.4%) with

negative cultures (P ≤0.001). In the IM group, 4 of the 5 patients (80%) with positive cultures had good adherence, with no significant difference from the patients in the

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same group with negative cultures (83/122, 68%).

Discussion

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A striking finding of the present study is the poor adherence to SPP among Israeli pediatric patients with rheumatic fever. Studies in both adults and children have

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shown that adherence to continuous medical regimens tends to decrease over time mainly when the regimens are prophylactic and the patients are usually

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asymptomatic.13,15-17 In the first year, relatively good adherence was noted in 28.2%

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of our patients, which is in line with the approximately one-third of patients reported by others.18 However, by the tenth year of follow-up, the PDC had exponentially

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deteriorated to 5.7%, even though there was still an absolute indication for SPP.

Oral SPP is not acceptable in other countries where rheumatic fever is endemic.10 Adherence is expected to be better with a monthly IM rather than a daily oral regimen that includes physician prescription refills and subsequent pharmacy claim. (At MHS, patients usually receive a one-month supply of the oral dose at each pharmacy refill).

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Nevertheless, this study shows that in Israel, the vast majority of children (87%) were prescribed oral SPP. It is likely that parents preferred this route because the IM administration of SPP is often a painful and traumatic for the child.19 Indeed, the PDC was significantly higher for oral SPP than for IM PDC in the first year (107.3 vs. 72.6 days, P<0.005), although the difference did not remain significant thereafter. It is

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important to note that according to the current guidelines6 the use of monthly IM

penicillin therapy is the preferred choice over the use of daily oral regimen for SPP

and that even with optimal patient adherence, the risk of GAS recurrence is higher in individuals receiving oral prophylaxis than among those receiving intramuscular

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benzathine penicillin.

Clinic-scheduling strategies to improve adherence include making follow-up visits

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convenient and efficient for the patient.18 We found that after a visit to a pediatric rheumatology clinic, the rate of patients with a PDC of >80% rose from 45.7% at 3

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months before a visit to 61.2% (P ≤0.06). Importantly, however, although the

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difference was significant, it accounted for a mere 15% increase in adherence, with more than half the patients who presented at the clinic failing to adhere to the

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treatment regimen. Therefore, a visit to a pediatric rheumatology clinic is not a

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sufficient measure by itself to increase adherence to SPP.

Finally, we examined the effect of SPP on the rate of GAS infection. Adherence to oral SPP had an overall protective effect against GAS infection, with only 6% of the adherent patients testing positive. By contrast, although the numbers are small, adherence to IM SPP did not necessarily provide protection against GAS: 4 of the 5 adherent patients in this group tested positive. These finding do not support the

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preference for IM over oral SPP as shown in other studies19, None the less, GAS carriage could not have been ruled out in any of the tested patients.

Large claim databases are increasingly being used in clinical and pharmacological research due to their potential to capture efficacy, safety and adherence trends in large

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populations and for extended periods of time and provide real-world data which has a unique significance in rare disease studies 20-22. Limitations of this study, as for any

large database study, 22 include the validation of rheumatic fever diagnosis. However, the use of at least one monthly dose of IM benzathine penicillin or of daily doses of

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oral penicillin for at least 28 days highly increases the likelihood and validity of the

diagnosis of rheumatic fever. In addition, our analysis was based on the assumption that dispensed medications were consumed and that patients did not purchase

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medication from a non contracted pharmacy. This assumption is logical due to the fact that in Israel, drugs sold in private pharmacies are not subsidized and are therefore

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more expensive than in pharmacies affiliated with recognized health management

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organizations. We are aware that a potential group of patients who never filled an SPP prescription might have been missed; however, this presumably small group only

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strengthens our conclusion regarding the poor adherence to SPP. Another potential limitation is the challenge of differentiation between patients with and without

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rheumatic heart disease including residual heart disease. The present results render both modes of long term prophylaxis futile, strongly indicating that new strategies to improve adherence to SPP are urgently needed.

Options include continued attempts to empower the child and family at each contact, education about rheumatic fever and rheumatic heart disease, and utilization of electronic medical records to alert primary care physicians to low PDC as an indicator

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of non-adherence .7, 9-10 Globally, sustained reengagement of clinicians, researchers, funders, and public health bodies are needed aiming towards elimination of this disease, including echocardiography-based screening program of populations at risk in order to start SPP before irreversible heart damage has occurred."

3, 23, 24.

GAS vaccine has been stalled by a combination of scientific, regulatory, and

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commercial barriers and unfortunately is still far from clinical utilization.25 Conclusion

By utilizing large medical database which enables 10 years' follow-up in over 800

patients with history of RF, we show that adherence to SPP and its persistent use is

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poor in the Israeli pediatric population with rheumatic fever. Oral SPP is preferred

over IM SPP presumably because its administration is painless and less upsetting to children. Although oral SPP is not recommended by the World Health Organization,

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we found no significant difference in coverage between the oral and IM route in any of the years of follow-up except the first. Moreover, according to this study, oral SPP

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may be more effective than IM SPP in the prevention of GAS.

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Poor adherence and persistence to SPP as found in Israel which is a developed country with an advanced medical system and excellent accessibility to health

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services26,27 , should alert clinicians in other developed countries who are endemic to

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RF .

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Desai M, Oppenheimer JJ. Medication adherence in the asthmatic child and adolescent. Curr Allergy Asthma Rep. 2011;11(6):454-464. 17. Joyce NR, Wellenius GA, Eaton CB, Trivedi AN, Zachariah JP. Patterns and predictors of medication adherence to lipid-lowering therapy in children aged 8 to 20 years. J Clin Lipidol. 2016;10(4):824-832.e2. 18. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-497. 19. Wyber R, Boyd BJ, Colquhoun S, Currie BJ, Engel M, Kado J, et al. Preliminary consultation on preferred product characteristics of benzathine penicillin G for secondary prophylaxis of rheumatic fever. Drug Deliv Transl Res. 2016;6(5):572-578. 20. McMahon AW, Dal Pan G. Assessing Drug Safety in Children - The Role of Real-World Data. N Engl J Med. 2018 Jun 7;378(23):2155-2157. 21. Chai G, Governale L, McMahon AW, Trinidad JP, Staffa J, Murphy D. Trends of outpatient prescription drug utilization in US children, 2002-2010. Pediatrics 2012;130:23-31. 22. Sharland M, Kendall H, Yeates D, Randall A, Hughes G, Glasziou P, et al. Antibiotic prescribing in general practice and hospital admissions for peritonsillar abscess, mastoiditis, and rheumatic fever in children: time trend analysis. BMJ. 2005;331(7512):328-329. 23. Marijon E, Celermajer DS, Jouven X. Rheumatic Heart Disease - An Iceberg in Tropical Waters. N Engl J Med. 2017 Aug 24;377(8):780-781. 24. Marijon E, Ou P, Celermajer DS, Ferreira B, Mocumbi AO, Jani D, Paquet C, Jacob S, Sidi D, Jouven X. Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med. 2007 Aug 2;357(5):470-6. 25. Osowicki J, Vekemans J, Kaslow DC, Friede MH, Kim JH, Steer AC. WHO/IVI global stakeholder consultation on group A Streptococcus vaccine development: Report from a meeting held on 12-13 December 2016. Vaccine. 2018 Jun 7;36(24):3397-3405. 26. Oliver J, Baker MG, Pierse N, Carapetis J. Comparison of approaches to rheumatic fever surveillance across Organisation for Economic Co-operation and Development countries. J Paediatr Child Health. 2015;51(11):1071-1077. 27. Rosen B, Waitzberg R, Merkur S. Israel: health system review. Health Syst Transit. 2015;17(6):1-212.

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Legend to Figure Figure 1.

(A) Mean daily SPP coverage (days covered in each year (365 days) for 10 years since SPP was initiated. (B) Oral regimens, in logarithmic scales. (C) IM regimen, in logarithmic scale. (D) Yearly comparison of oral vs. IM regimen

Figure 1A:

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Days covered with SPP

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Years since index date

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Figure 1B:

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Years

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oral PDC

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Figure 1C:

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IM PDC

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Years

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Figure 1D:

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Injection

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Days covered with SPP

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Years since index date

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Table 1. secondary penicillin prophylaxis regimens used for RF patients

Initial therapy

No. of patients

Percent of group

Percent of cohort

Penicillin VK

423

57.60%

50.20%

Amoxicillin

203

27.70%

Amoxicillin

2.70%

87

Sulfadiazine

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Intramuscular regimen (n=108) Benzanthine

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108

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penicillin G

2.40%

11.90%

10.30%

0.10%

0.10%

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trihydrate Macrolides

24.10%

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Oral regimens (n=743)

100.00%

12.80%

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Table 2. Proportion of days covered for secondary prophylaxis before and after a visit to a pediatric rheumatology clinic Route of SPP 3 months before visit

3 months after visit

administration PDC >80%a

N

PDC >80%a

Oral

60

27 (45%)

67

39 (58.2%)

IM

21

10 (47.6%)

18

13 (72.2%)

Total

81

37 (45.6%)

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PDC, proportion of days covered; IM, intramuscular

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PDC >80% defined as good adherence

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<0.16 <0.19

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N

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P value

52 (61.2%)

<0.061

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Table 3. Results of GAS cultures obtained during the study period by proportion of days covered values at 3 months before the cultures were obtained Positive culture

Negative culture P value

PDC >80%

N

PDC >80%

Oral

49

3 (6.1%)

371

187 (50.4%)

<0.001

IM

5

4 (80%)

122

83 (68%)

<1.0

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GAS, group A Streptococcus; PDC, proportion of days covered; IM, intramuscular