JDBT Journal

Introduction

Diabetes is a major burden on the health of populations worldwide. According to the International Diabetes Federation ATLAS, in 2021 an estimated of 537 million adults aged 20– 79 years are currently living with diabetes worldwide which represents 10.5% of the world’s population in this age group [1]. This number is predicted to rise to 783 million in 2045 with standardised prevalence to each national population of 12.2% [1]. People with T2D are at substantially increased risk of developing complications, both macrovascular (coronary heart disease and stroke) and microvascular (retinopathy and nephropathy).

Hypertension is present in half of patients with T2D at diagnosis, with hypertension developing later in the course of the disease in most of remaining patients. When combined with hypertension, diabetes risk of developing complications increases. The most common and potentially devastating complication of diabetes is chronic kidney disease (CKD). An approximate 40% of people with diabetes have CKD and CKD associated with diabetes is the leading cause of kidney failure in Canada [2,3]. Classic diabetic nephropathy progresses over many years from subclinical disease (microalbuminuria, MA) to overt nephropathy (with lowering of eGFR) to end-stage renal disease, to dialysis and renal transplantation presenting a significant burden in Canada with over 4 million Canadians suffering from chronic renal diseases [4].

Progression of diabetic nephropathy can be slowed down with medications that disrupt the renin-angiotensin-aldosterone system [5]. In T2D patients, Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARB) have been shown to decrease albuminuria, prevent worsening of nephropathy and reduce the risk of developing new nephropathy [6-8]. In ADVANCE trial, ACEi based therapy was able to achieve most significant primary prevention of microalbuminuria [9]. This intensive control of blood pressure to <135/85 resulted in lowering total mortality in this clinical trial [10]. Over last few years, novel classes of medication, including sodium glucosecotransporter type 2 inhibitors, glucagon-like peptide-1 receptor agonist and selective, non-steroidal mineralocorticoid receptor antagonist, were demonstrated to decrease and prevent renal as well cardiovascular events. The combination of cardiovascular and kidney complications  has become known as cardiorenal complication [11-13]. It has been shown that urinary albumin to creatinine ratio (UACR) is the most efficient modifiable traditional risk factors to predict cardiovascular mortality, heart failure, and stroke in the general population [14]. Although a good predictor of cardiovascular mortality, eGFR was not found to be as good as UACR particularity due to its initial non-linear risk impact.

The current recommendation is to measure UACR at the diagnosis of T2D and yearly thereafter, when no other causes of albuminuria or low estimated glomerular filtration rate (eGFR) are present, and when acute renal failure or non-diabetic kidney disease is not suspected [15]. In addition, persistent microalbuminuria, defined by at least 2 of 3 tests positive taken at 1- to 8-week intervals, should be demonstrated before the diagnosis of nephropathy is made.

American Diabetes Association signals the importance of therapeutic inertia in T2D by not achieving well demonstrated targets, recommended by advisory bodies and the need to improve the status quo [16,17].

Point of care testing (POCT) HemoCue is a device allowing immediate testing found to be sufficiently accurate correlating with laboratory estimations. Preliminary evidence of the POCT benefit in diabetes outpatients already exist. Heidkamp et al. examined whether systematic screening for urine albumin using a POCT in outpatients with diabetes increased the frequency of the diagnosis of nephropathy [18]. The study was conducted in 15 primary physicians’ offices in 2002 (12 months) as control versus 2003 (3 months) when HemoCue Urine Albumin® POCT was available, on a total of 2211 diabetic outpatients. In the control group, 15% of patients were diagnosed with microalbuminuria compared 41% during 3 months when using HemoCue. The authors concluded that systematic examinations of urinary albumin by the HemoCue Urine Albumin® POCT result in a higher frequency of diagnosis of nephropathy [18].

Our objective was to assess whether a point-of-care testing of albuminuria in management of hypertensive T2D patients could help overcome therapeutic inertia by providing physicians with a point of care measure of blood pressure and albuminuria [17] to improve treatment. Further objective was to evaluate the impact of POCT on the rate of diagnosis of albuminuria or CKD. Finally, overall satisfaction of health care professionals was also monitored.

Methods

Clinpradia study was a multicenter stepped wedge cluster randomized trial of family practice clinics in Quebec and Ontario comparing the effect of introducing at different times a POCT for urine albumin to usual practice on quality of care in hypertensive patients with T2D. The study was performed at 8 sites with at least 5 General Practitioners (GPs) in each clinic: 4 Groups of Médecine Familiale (GMF) in Quebec and 4 Family Health Teams (FHT) in Ontario with at least 35 patients per clinic. The objective was to recruit a total of 280 subjects over a period of 3 months. The recruitment period had to be extended to 6 months. Inclusion criteria included T2D adults (>18 years) male or female with ongoing anti-diabetic therapy for at least 5 years and uncontrolled hypertension (i.e. BP>130/80 mmHg). Patients signed informed consent form for conduct of this study that was approved by ethics committee of coordinating center and by each participating clinic. The data analysis was approved by the ethics committee of the Centre Hospitalier de l’Université de Montréal (CHUM). Patients with type 1 diabetes or who were already on therapy used in ADVANCE trial or allergic to ACEi or sulfonamide derivatives were excluded from the study. Other exclusion criteria were severely impaired renal function, angioedema related or not to previous treatment with ACEi, hyperkalemia or hypokalemia, severe hepatic impairment, use of non-antiarrhythmic agents causing torsade de pointes, pregnant or lactating women and any other conditions which may impact on participation according to treating physician.

Data were collected at entry and at each visit occurring every 3 months for a period of one year. Three clinical sites in Quebec and 3 in Ontario were randomly assigned to the intervention group. The sites in Ontario were Welland McMaster Family Health Team, Albany medical clinic and Stoney Creek. The sites in Quebec were Clinique du Centre Médical des Générations, Clinique médicale Angus, and Fleury. One site in Ontario (Kingston Family Health Team clinic) and one in Quebec (Clinique médicale MaisonneuveRosemont) were assigned to the control group.

In the sites allocated to POCT, patients underwent a measure of their urinary albumin excretion using POCT, on the morning urine or urine spot, just before their appointment with their treating physician accompanied by their blood pressure results as well as CHEP guidelines of recommended BP and albuminuria targets. A urine sample was also collected at baseline and at each visit (5 collections). These urine samples were frozen and were sent to a central laboratory for the determination of ACR at the end of the study for the estimation of the correlations between urine albumin measured by POCT and laboratory determined UACR.

Before the study, participating physicians attended an investigator meeting during which CHEP guidelines for the management of hypertension in diabetic patients were refreshed and study objectives [19], design and procedures were explained. The results of the ADVANCE trial were also discussed during that meeting [20].

A total of 249 subjects were enrolled in the clinical study. Of those, 4 patients were excluded from analysis because one site closed just after the start of the study and 2 were excluded because they did not meet the inclusion criteria. Patient attrition during the study was as follow: 10 patients withdrew and one deceased after baseline visit. 6 patients withdrew, 2 missed their visit and one patient deceased after the second visit. 4 patients withdrew after the third visit and 3 patients missed their visit. Finally, 8 patients missed their final visit or withdrew from the study after the fourth visit. 213 patients were followed until the end of the study.

Statistical Analyses

Results are presented as mean and SE for continuous variables with normal distribution and as numbers and percentage for categorical variables. Baseline characteristics p values were calculated using chi-squared test or one-way analysis of variance, as appropriate. Difference in number of patients with albuminuria or with hypertension p values were evaluated using the Fisher’s exact test or McNemar’s test, as appropriate. P values of the mean difference between treatments were calculated using paired t-test and by Wilcoxon paired test for median differences between interventions. Logarithms of ACR values were analyzed because ACR value did not follow a normal distribution. All p values were statistically adjusted using the variance inflation factor (VIF). The VIF was calculated from the intraclass correlation coefficient. A value of p<0.05 was considered statistically significant. Analyses were made using R statistical software version 1.2.1335 (R core team, 2019) [21].

Results

Performance of the POCT HemoCue device in detecting albuminuria

The measures between the POCT albumin values and laboratory ACR results were correlated confirming the validity of using this point of care device (Table 1). The mean Pearson correlation coefficient calculated at each visit between the ACR (mg/mmol) and the POCT urine albumin values (mg/L) was 0.47 and was statistically significant at each visit (Table 1). As the POCT could not differentiate between micro and macro albuminuria, the two were combined and compared to normoalbuminuria for the laboratory ACR values. Taking the laboratory ACR value as the standard, the POCT test exhibited an average positive predictive value of 62% and a negative predictive value of 90% along the visits. The sensitivity and specificity of the POCT in detecting albuminuria were 88% and 67%, respectively over one-year period.

Table 1: Performance of the POCT to predict albuminuria status

Effect of the introduction of blood pressure and albuminuria at the clinical sites

The baseline characteristics of participants are depicted in Table 2. The mean age of 66.5 years was not different between the intervention and control groups (P trend=0.663). There were more men than women in both groups. At baseline, 91% of patients had a blood pressure over 130/80 mmHg with an average systolic blood pressure of 144 mmHg and an average diastolic blood pressure of 78 mmHg in the total sample (Table 2). At entry, 36% of participants had albuminuria and 74% had an HbA1c>6.5%. 84% of hypertensive T2D patients in the study were already treated for hypertension with 1.75 medication classes on average. These results highlight therapeutic inertia when the therapeutic targets are not met.

Table 2: Baseline demographic and clinical characteristics.

The decrease in log ACR from 0.357 to 0.017, between first and last visit, was highly significant (p=0.0002) in the intervention group while it was not significant (p=0.227) in the control group (Figure 1). By the end of the study, the percentage of patients with albuminuria decreased significantly (p=0.030) by 26% in the intervention group while it increased by 30% (p=0.092) in the control group (Table 3).

Table 3: Albuminuria and hypertension patient status changes between baseline and last visit.

Figure 1: Mean of Logarithm of urinary albumin creatinine ratio (LogUACR) at visit 1 (V1, baseline) and visit 5 (V5, 12 months) for control and intervention groups. NS, not significant.

At the beginning of the study, the average SBP was similar between the two groups (Figure 2). Over the course of the study, the decrease in SBP was more important in the intervention group, so that at the end, the average SBP was 129 mmHg in the intervention and 137 mmHg in the control groups, with a significant difference between the two (p=0.004). Hence, the decrease in the number of patients with uncontrolled hypertension was highly significant in both groups but the percentage of participants with uncontrolled  hypertension at the end of the study was lower in the intervention group (50%) than the control group (63%) group (Table 3).

Figure 2: Mean systolic (A) and diastolic (B) blood pressures at each visit for both compared control and intervention groups. p-value based on ANOVA test. V, visit.

Effects of prescribed medication on BP, albuminuria and eGFR

The mean systolic blood pressure decreased significantly in all participants who received an ACEi or an ARB alone or in combination with a CCB (Figure 3A). The decrease in ACR was only significant with the combination of an ACEi or an ARB with CCB (p<0.01, Figure 3B). The decline of eGFR in patients who were taking an ACEi or an ARB was overcome by their combination with a CCB (Figure 3C).