The uptake and outcome of the initial screening is shown in . A total of 1918 eligible patients were identified from the diabetes mellitus and ischaemic heart disease registers of the participating practices and invited to attend for venesection. Initial uptake was 40% (95% confidence interval [CI] = 37% to 42%) overall, but higher in Oxfordshire (477/966, 49%) than in Birmingham (282/952, 30%). About one in five patients tested (147/759, 19%) had a raised natriuretic peptide (BNP or NTpro-BNP) on the first test, but 40% (53/132 retested × 2) did not have a persistently raised BNP >43.3 pmol/l on further investigation. Of the 79 patients in whom BNP remained elevated, 76 entered treatment titration. One patient was withdrawn because of mitral stenosis recognised on echo assessment, one because of comorbidity, and the third because of known intolerance to a drug in the titration regime.
Outcome of initial invitation to BNP screening of the 1918 patients on the diabetes and ischaemic heart disease morbidity registers.
Baseline characteristics of patients titrated
The mean age of the 76 patients offered treatment titration was 77 years (range 66–92 years), and the mean entry BNP (the mean of the confirmatory screening sample and the pretreatment sample) was 62.4 pmol/l (range 37.5–144.1 pmol/l). Most patients were either asymptomatic (23, 30%) or had only mild symptoms of heart failure (41, 54%); the remaining 12 patients had more marked symptoms, with a NYHA score of 3. Most patients (49, 65%) were assessed as having neither global nor regional ventricular systolic dysfunction on echocardiography, with only 11 (14%) having an ejection fraction <40%. shows that more than one-third of patients (40%) were already receiving the recommended treatment for ventricular dysfunction of both an angiotensin inhibitor and beta-blocker; few (13%) were receiving neither.
Medication prescribed at the beginning and end of BNP-guided treatment titration (n = 76).
Changes in medication made during titration
The mean number of visits made by each patient for assessment and titration of treatment was 8.6 (standard deviation [SD] 2.9) and median 9 (interquartile range [IQR] 7–11). The minimum of visits was five. shows that the proportion of patients receiving optimal treatment (that is, both an angiotensin inhibitor and a beta-blocker) increased from 40% to 74%, and the proportion receiving neither treatment fell from 13% to 5%. The most common adjustments made during the first three visits were the introduction or up-titration of angiotensin inhibitors (81 titrations), the introduction or up-titration of a beta-blocker (33 titrations), or a change in beta-blocker (27 switches, in 26 cases a switch to carvedilol or bisoprolol). The decision to switch beta-blockers was region specific: 24 of the 27 switches were in Oxford practices. Introduction of spironolactone was infrequent (five events).
Effect of titration on BNP
The effect of titration on the BNP concentration is shown in . Twenty-one patients (28%) were within the BNP target range (<36 pmol/l) at exit. The mean BNP reduction achieved was 10.8 pmol/l (17%, P<0.001). Most of the reduction achieved was the result of initial modification of treatment rather than continuing titration — the BNP concentration at visit 2 was 52.6 pmol/l, and at exit 51.6 pmol/l.
Figure 2 Blood BNP concentrations (pmol/l) at entry (mean of two pre-titration samples), at exit (mean of last two samples), and at first four intermediate titration visits. Data below x axis show mean BNP concentrations and proportion of patients within target (more ...)
The stepwise approach to the mixed-effects regression provided a final model that included both switching to bisoprolol or carvedilol, and introducing or up-titrating the angiotensin inhibitor as significantly associated with reduction in BNP. Switching to bisporolol or carvedilol, in most cases from atenolol, was the most significant titration step in the regression model (β coefficient 20.0, P = 0.001), with the introduction or up-titration of an angiotensin inhibitor having less effect (β coefficient 9.8, P = 0.037). The effect of up-titration of beta-blockers was not statistically significant.
There was a substantial difference in the reduction in BNP achieved by practices clustered around Oxford compared to those around Birmingham. The mean fall in BNP in the Oxford practices was 17 pmol/l compared to 0 pmol/l in the Birmingham practices (P<0.001). This contradicted the prior hypothesis that Oxfordshire practices would perform less well because of higher pretreatment prescribing rates of angiotensin inhibitors and beta-blockers. The multiple regression analysis suggests that the explanation lies in drug titration practice, particularly switching of beta-blockers, as the effect of region (Oxford or Birmingham) on BNP was not significant after adjustment for the titration steps.
Difficulties and adverse effects of treatment titration
Three-quarters of patients starting the titration (57/76, 75.0%) completed it as recommended (that is, until within the BNP target range of <36 pmol/l or 6 months had elapsed), although few complied strictly with the planned 2–4-weekly visit timetable for treatment adjustment. shows that clinicians did not adjust medication at every visit as anticipated by the titration schedule — by the fourth visit the mean number of titration steps made was only 1.9, and by exit 3.1. In eight patients, no change was made in medication at all. In a further 11 patients, titration was interrupted because of new episodes of illness (six patients), or patient unwillingness to continue (five patients). One patient recorded a confirmed potassium concentration >5.5 mmol/l, which required withdrawal of spironolactone. Two patients recorded a creatinine above 200 μmol/l, but only in one case related to uptitration of an ACE inhibitor. Titration was stopped in two patients because of suspected hypotensive episodes; in one episode a patient fell while dismounting their bicycle and fractured a femur; the admitting clinician mentioned hypotension in the discharge summary as a possible precipitating cause.