Effectiveness and safety of the tetanus vaccine by intramuscular versus subcutaneous route in anticoagulated patients. Randomized clinical trial in primary care.

Ana Clavería, Fernando Lago-Deibe, Clara González-Formoso, María Victoria Martín-Miguel

Keywords: clinical trial, vaccine effectiveness, safety.

In patients treated with oral anticoagulants, subcutaneous injections of anti-tetanus vaccine are usually recommended to reduce the risk of bleeding, although the effectiveness of the vaccine has only been proven for intramuscular injection.

Research questions:
Are subcutaneous injections of tetanus-diphtheria vaccine as effective and safe as intramuscular route in patients treated with oral anticoagulants?

DESIGN: Prospective, double blinded, clinical trial, comparing tetanus-diphtheria vaccine routes, intramuscular (im) vs subcutaneous (sc) injection, in patients with oral anticoagulants. Randomized allocation.
STUDY POPULATION: Patients treated with oral anticoagulants, with at least one dose of vaccine, at 15 Health Centres in Vigo (Spain). Sample size stimated: 115 patients in each group.
OUTCOME VARIABLES: For effectiveness analysis: differences in antibodies titers against tetanus toxoid. Independent variables: route, sex, age, basal serology, number of doses administered. For safety analysis: systemic reactions and, at the vaccine administration site, brachial diameter, eritema and pain.
ANALYSIS: Multivariate logistic regression for safety, multivariate regression with repeated measures, for effectiveness. Intention-to-treat analysis was performed.
Trial registration: ISRCTN69942081.
Clinical Research Ethics Committee approval on 07/06/2007, with 2007/089. Grant from the Consellería de Sanidade of Galicia (Spain), No. PS07/114.

117 im / 117 sc. 102 women / 132 men. 75% one dose administered. No difference between groups in any independent variable. Duration of the study was six years. Protocol was followed.
For effectiveness, there were adjusted significant differences only by basal serology.
Considering safety, just one systemic reaction. Locally, there were adjusted significant differences in pain by sex (female, protective) and route (sc, 0.55 (0.31-0.97)); in eritema, by sex (female, protective) and route (sc, 5.19 (1.87-14.41)); in tumefaction, by sex (female, protective) and route (sc, 2.74 (1.19-6.32)).

There were no adjusted significant differences in effectiveness by route. There were adjusted differences in local reactions, by sex and route.
Patients preferences should be considered.

Points for discussion:
Difficulties in clinical trials in primary care: recrutiment, follow-up, monitorization, insurance.

Patient preferences as outcome.

Difficulties in multicentric studies: standardization, records mangement, documentation.