| Summary: | Background Acute rheumatic fever (ARF) and rheumatic heart disease cause substantial burdens worldwide. Long‐term antibiotic secondary prophylaxis is used to prevent disease progression, but evidence for benefits of different adherence levels is limited. Using data from northern Australia, we identified factors associated with adherence, and the association between adherence and ARF recurrence, progression to rheumatic heart disease, worsening or improvement of rheumatic heart disease, and mortality. Methods and Results Factors associated with adherence (percent of doses administered) were analyzed using logistic regression. Nested case–control and case–crossover designs were used to investigate associations with clinical outcomes; conditional logistic regression was used to estimate odds ratios (OR) with 95% CIs Adherence estimates (7728) were analyzed. Being female, younger, having more‐severe disease, and living remotely were associated with higher adherence. Alcohol misuse was associated with lower adherence. The risk of ARF recurrence did not decrease until ≈40% of doses had been administered. Receiving <80% was associated with a 4‐fold increase in the odds of ARF recurrence (case–control OR: 4.00 [95% CI: 1.7–9.29], case–crossover OR: 3.31 [95% CI: 1.09–10.07]) and appeared to be associated with increased all‐cause mortality (case–control OR: 1.90 [95% CI: 0.89–4.06]; case–crossover OR 1.91 [95% CI: 0.51–7.12]). Conclusions We show for the first time that increased adherence to penicillin prophylaxis is associated with reduced ARF recurrence, and a likely reduction in mortality, in our setting. These findings can motivate patients to receive doses since even relatively low adherence can be beneficial, and additional doses further reduce adverse clinical outcomes.
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