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ORIGINAL PAPERS: Organ damage assessment

Target organ damage assessment in French hypertensive patients without established cardiovascular or renal disease

results of the PREVENT-A study

Rossignol, Patricka,b,c,d; Hosseini, Kossare,f,g; Tropeano, Anne-Isabelleh; Fay, Renauda,b,c,d; Tsatsaris, Annei; Guillemin, Francise,f,g; Mounier-Vehier, Clairej,h

Author Information
doi: 10.1097/HJH.0b013e32835a34bb

Abstract

INTRODUCTION

Target organ damage (TOD) assessment is recommended by international guidelines in order to define the overall cardiovascular risk beyond traditional risk factors. Such assessments are to be performed in hypertensive patients not only before treatment (in order to stratify risk) but also during therapy because of the evidence that regression of left ventricular hypertrophy (LVH) and reduction of proteinuria indicates treatment-induced cardiovascular protection [1,2]. The significance of TOD in determining calculation of overall risk is dependent on how carefully the damage is assessed, based on available facilities [1,2]. The latest European Society of Hypertension (ESH)/European Society of Cardiology (ESC) 2007 guidelines proposed a list of tests, with a focus on new parameters such as carotid-femoral pulse wave velocity (PWV) and ankle/brachial blood pressure index (ABI). The list of renal markers of organ damage was also globally expanded to include the estimates of creatinine clearance by the Cockcroft–Gault formula or of glomerular filtration rate (GFR) by the modification of the diet in renal disease. In addition, microalbuminuria was now considered as an essential component in the assessment of organ damage because its detection is easy and relatively inexpensive [1,2]. Whenever possible, the recommendation was made to measure organ damage in different tissues (e.g. heart, blood vessels, kidney and brain) because multiorgan damage is associated with a worse prognosis [1,2]. To date, the implementation of ESH/ESC 2007 guidelines with regard to TOD assessment has not been evaluated in treated hypertensive patients without established cardiovascular disease, that is patients especially prone to benefit from a cardiovascular risk assessment reclassification upon subclinical TOD assessment. It was recently shown in unselected hypertensive patients from Central and Eastern European countries (50.7% with a history of coronary disease, 11.5% with a history of stroke) that electrocardiogram (EKG) evaluation was performed in 98.8% of patients and echocardiography and funduscopy in 64.5 and 67.8% of patients, respectively. Carotid ultrasound was performed rarely (24.1%) and assessment of microalbuminuria even more scarcely (10.0%) [3]. However, the fact that the majority of these patients were secondary prevention patients may have influenced subclinical TOD assessment. In the present study, we aimed at evaluating the modalities of subclinical TOD assessment in France, 2–3 years after publication of the ESH/ESC 2007 guidelines, by conducting two large, cross-sectional studies in a representative sample of private practice cardiologists on the one hand and of general practitioners (GPs) on the other hand, in hypertensive patients without an established cardiovascular or renal disease.

MATERIALS AND METHODS

Two parallel, cross-sectional surveys were conducted in 2009–2010 in representative samples of French private practice cardiologists (‘PREVENT-A-C’) and GPs (‘PREVENT-A-GP’) with the primary aim to assess the frequency of subclinical TOD assessment and its modalities in hypertensive patients without a known established cardiovascular or renal disease, as defined by the ESH/ESC guidelines [1], and dichotomized according to blood pressure control (i.e. SBP <140 mmHg and DBP <90 mmHg, except for diabetic participants: SBP <130 mmHg and DBP <80 mmHg) [1].

Physicians

PREVENT-A-C

An enrolment of 600 cardiologists was initially anticipated among 2500 preselected upon prefeasibility assessment (expected a high proportion of hypertensive patients and/or previous survey participations), after regional adjustment, from a national registry of 6162 private practice cardiologists, with an expected acceptance rate of one in four. Study participation was proposed by phone, in a random order, in order to obtain 750 agreements to participate (May 2009), with 600 physicians finally actively participating, that is having sent at least one patient questionnaire. Ultimately, 516 cardiologists were considered as active.

PREVENT-A GP

An enrolment of 1250 GPs (1000 actively recruiting) was anticipated among 5000 preselected upon prefeasibility assessment (expected high proportion of hypertensive patients and/or previous survey participations) after regional adjustment from a national registry of 58 004 GPs, with an expected acceptance rate of one in five. Study participation was proposed by phone, in a random order, in order to obtain 1250 agreements to participate, with 1000 physicians finally actively participating, that is having sent at least one patient questionnaire. Ultimately, 943 GPs were considered as active.

For both surveys, the physician's representativeness with regard to the French medical population was assessed posthoc, by comparison with the Directorate for Research, Studies, Assessment and Statistics of Ministry of Health registry of French physicians demographics, and was found to be acceptable (data not shown) [4].

Patient inclusion criteria

The physicians were asked to recruit the first two consecutive patients during 1–2 weeks (June–November 2009: cardiologists; January–June 2010: GPs), which fulfilled the following inclusion criteria: male or female participants older than 18 years of age, consenting to participate after provision of information by the physician (under an obligation to keep data confidential, as required by the ‘Commission Nationale Informatique et Libertés’, which approved the surveys), with a known hypertension, treated or not. Exclusion criteria were hypertension diagnosed during the survey consultation and established cardiovascular or renal disease, as defined by the 2007 ESH guidelines [1], namely:

  1. Cerebrovascular disease: ischaemic stroke; cerebral haemorrhage, transient ischaemic attack;
  2. Heart disease: myocardial infarction; angina; coronary revascularization; heart failure;
  3. Renal disease: diabetic nephropathy; renal impairment (serum creatinine men>133 μmol/l, women >124 μmol/l); proteinuria (>300 mg/24 h);
  4. Peripheral artery disease: lower limb or carotid peripheral arterial disease, arterial aneurysm;
  5. Advanced retinopathy: haemorrhage or exudates, papilloedema.

Measurements

For each physician, data collection consisted in age, sex and city.

For each patient, data collection consisted in demography (age, sex, social status as defined by the French National Institute of Statistics), hypertension assessment: year of diagnosis, routine office blood pressure measurement, with a written reminder of the recommended methodology by the French ‘Autorité de Santé’ Guidelines (i.e. mean of two measurements, performed several minutes apart in a supine or sitting position) [5], type of device used (semi-automated or sphygmomanometer), height, weight, BMI (kg/m2), waist circumference, and family and personal history. Lastly, the following biological parameters within 1 year were recorded, when available, together with its date of sampling: fasting glucose (mmol/l), total and high density lipoprotein (HDL) cholesterol, and triglycerides.

TOD was assessed as follows, according to the available parameters during the year preceding the consultation:

  1. Heart assessment: LVH assessment, as evaluated by EKG or echocardiography.
  2. Vascular assessment: Cardiologists: ABI less than 0.9, PWV greater than 12 m/s, presence of carotid atherosclerotic plaques or carotid intima–media thickness greater than 0.9 mm, augmented abdominal aortic diameter, presence of atheromatous plaque in lower limb arteries. GPs: pathological ABI, or pathological PWV, or vascular abnormalities (i.e. plaques) in carotid or abdominal or lower limb ultrasound.
  3. Renal assessment: serum creatinine, GFR (estimated using the MDRD formula equation) [6], proteinuria (labstick or quantitative assessment), microalbuminuria.
  4. Retinopathy investigation, with the presence of hypertensive or diabetes associated abnormalities.
  5. Cerebrovascular assessment, with its modalities [MRI, computed tomography (CT) scan].
  6. Antihypertensive treatments as well as antiplatelet, anticoagulants, diabetes, lipid lowering agents were also recorded.

Cardiovascular risk evaluation

First, cardiovascular risk was estimated from the 2007 ESH/ESC tables for patients. Second, patients were reclassified according to the cardiovascular risk calculated with TOD searches and results expressed as an upgrading in cardiovascular risk.

Cost evaluation of target organ damage assessment

We quantified direct costs of each TOD assessment strategy from the perspective of the National Health insurance, which funds care providers. All costs are reported in Euros and were obtained from the Common Classification of Medical Acts (CCAM) and the Nomenclature of Medical Biology Procedures (NABM), which is determined by the public authorities and reflects the level of use of human and material resources for a given procedure. We assumed the cost of physicians to be constant for all patients; costs were included in the evaluation only for cases of TOD searches that required the intervention of an additional physician. We calculated the number needed to explore for benefit (NNEB, similar to the number needed to treat for benefit in head-to-head trials) as the ratio of the number of searches performed to the number of TOD identified (rounded to the upper unit). The mean cost of a TOD identified was computed as the product of the mean cost of the search by the corresponding NNEB. The mean cost of TOD assessment per patient for different cardiovascular risk classes according to ESH/ESC 2007 guidelines was also calculated.

Statistics

Data are expressed as mean ± standard deviation (SD) or as percentage values. Rates of TOD assessments in subgroups of patients with controlled and uncontrolled blood pressure were compared using the chi-square test or Fisher exact test when appropriate. Effect of age (stratified according to the median) on association between hypertension control and TOD searches was assessed using the Breslow–Day test for homogeneity of odds ratios.

All analyses were performed using SAS 8.2 release or later (SAS Institute, Cary, North Carolina, USA). The two-tailed significance level was set at P value of less than 0.05.

Sample size calculations

PREVENT-A-C

Assuming a prevalence of 50% for TOD, of 40% for controlled hypertension [7–10] in France from the latest available data and of 20% for nonusable observations, a sample size of 1200 patients would allow to determine TOD proportion with an accuracy equal to or better than 5% (95% confidence interval, CI: ±5%).

PREVENT-A-GP

Assuming a prevalence of 40% for TOD, of 35% for controlled hypertension in France [7–10] from the latest available data and of 20% for nonusable observations, a sample size of 2000 patients would allow to determine TOD proportion with an accuracy equal to or better than 4% (95% CI: ±4%).

Cost analysis

A statistical univariate analysis was performed to describe the cost of each TOD search with mean (SD) and 95% CI for cardiologists and GPs. The mean cost of each TOD strategy by cardiovascular risk according to the ESH/ESC 2007 guidelines was compared using analysis of variance (ANOVA).

A multivariate linear regression analysis further investigated the manner in which the number of TOD searches influenced the total cost of TOD assessment for cardiologists and GPs. Both models were adjusted for age, sex, comorbidities and estimated cardiovascular risk.

RESULTS

Study participants

In total, 516 cardiologists enrolled 952 analysable patients, and 943 GPs enrolled 1778 analysable patients (Fig. 1: flow charts). As summarized in Table 1, patient characteristics were very similar, with a mean age of 61.6 (PREVENT-A-C) and 60.7 years (PREVENT-A-GP), sex ratio of approximately 3 : 2 (men/women), BMI of 27.8 and 27.7 kg/m2, with 17.5 and 18.1% diabetic patients, and a blood pressure control rate of 29.1 and 33.2%, respectively.

FIGURE 1
FIGURE 1:
Surveys flow-charts. GP, general practitioner.
TABLE 1
TABLE 1:
Patient characteristics in the respective cardiologists’ and general practitioners’ surveys

Target organ damage assessments

At least one TOD search was performed in 97.6% of cardiologists’ patients, performed or ongoing in 96.1% of GPs’ patients, with a median number of three TOD searches in both surveys (Table 2). Only 8.6% of cardiologists’ patients and 6.3% of GPs’ patients had a full set of TOD analyses (i.e. the five categories investigated: LVH, vascular, renal, retinopathy and cerebrovascular). When considering the associations of subclinical TOD search in patients with at least two searches (Table 3), and the three priority categories recommended by the ESH guidelines (i.e. LVH, vascular, renal), 63.2% of cardiologists’ patients and 49.5% of GPs’ patients underwent this triple assessment.

TABLE 2
TABLE 2:
Number of subclinical target organ damage assessments in both surveys
TABLE 3
TABLE 3:
Subclinical target organ damage assessment associations (A: Cardiologists, B: GPs) in patients with at least two assessments

Patients were additionally subdivided with regard to their blood control status, as prespecified by the protocol. When taking into consideration the five different subclinical TOD categories, both groups only differed in terms of LVH search for cardiologists’ patients (92.2% in uncontrolled hypertension vs. 96.6% in controlled hypertension, P = 0.017), and in cerebrovascular evaluation for GPs’ patients (11.5 vs. 8%, P = 0.026) (Fig. 2). There was no significant effect of age on association between hypertension control and TOD searches.

FIGURE 2
FIGURE 2:
Target organ damage assessment by cardiologists (a) and GPs (b), as a function of the blood pressure control. TOD, target organ damage.

LVH assessment with electrocardiogram or echocardiography was performed in 93.5% of cardiologists’ patients and was performed or ongoing in 65.3% of GPs’ patients.

Vascular assessment

At least one vascular assessment was performed in 68.6% of cardiologists’ patients: this included carotid (51.9%) (with intima–media thickness measurement in 10.3% only), lower limb (27.9%) and abdominal aorta (39.5%%) ultrasound scans, and ABI (25.9%) and PWV (4.9%) measurements. At least one vascular assessment was performed or ongoing in 46.5% of GPs’ patients: this included carotid (69.3%), lower limb (57.7%) and abdominal aorta (43.4%) ultrasound scans, and ABI (16.0%) and PWV (2.1%) measurements.

Renal assessment

Among the 78.8% of cardiologists’ patients with one renal TOD search, serum creatinine was measured in 91.5%, proteinuria by labstick in 39.1%, quantitative proteinuria in 9.6% and microalbuminuria in 20.8%. Among the 92.4% of GPs’ patients with one performed (92.1%) or ongoing (0.3%) renal TOD search, serum creatinine was measured in 97.9%, proteinuria by labstick in 33.3%, quantitative proteinuria in 13.2% and microalbuminuria in 20.2%.

Hypertensive or diabetic retinopathy was investigated in nearly half of the patients in both surveys (49.7% in cardiologists’ and 50.1% in GPs’ patients).

A cerebrovascular TOD was rarely searched for in both surveys: 13.1% of cardiologists’ patients (84.0% by brain MRI) and 10.2% in GPs’ patients (19.8% by brain MRI, 38.5% by CT scan).

Cardiovascular risk assessment

Irrespective of the number of TOD searches considered, only 3.3% (58/1740) of GPs’ patients and 15.4% (142/925) of cardiologists’ patients were reclassified with an upgraded cardiovascular risk. Further exploration of reclassification improvement associated with the number of TOD searches was also performed. Analyses revealed a trend towards an increase in both surveys and that the ESH/ESC-recommended search association (LVH–vascular–renal) showed the greatest effectiveness in upgrading the cardiovascular risk (Online supplemental data Tables 1–4, https://links.lww.com/HJH/A206).

Cost analyses

The total mean cost of TOD assessment per patient was €171.2 (±100.8) for cardiologists and €112.6 (±74.9) for GPs. LVH assessment had the highest mean cost per patient for both cardiologists and GPs and was €89.6 (±24.8) and €57.8 (±47.2), respectively. In GPs, cerebrovascular assessments displayed the lowest costs [€7.5 (±38.3)] per patient, whereas in cardiologists, retinopathy searches were the least costly [€9.4 (±12.1)] (Table 4).

TABLE 4
TABLE 4:
Comparison of mean costs of target organ damage searches (in €) per patient by cardiovascular risk according to the European Society of Hypertension/ European Society of Cardiology 2007 guidelines for both general practitioners and cardiologists

The mean cost per patient of each TOD assessment considered separately was significantly higher for patients with a high or very high cardiovascular risk in GPs only (Table 4).

From a multivariate regression model, the average cost per patient for each additional TOD assessment increased by €45.3 (P < 0.0001) in GPs and by €62.3 (P < 0.0001) in cardiologists.

In GPs, the highest mean cost for one identified TOD was for LVH assessment, that is €462.8 in eight patients needed to identify one LVH (Table 5), whereas for cardiologists, cerebrovascular assessment in 18 patients needed to identify one TOD displayed the highest mean cost (€563.4).

TABLE 5
TABLE 5:
Mean cost of a target organ damage identification

DISCUSSION

To the best of our knowledge, this is the first survey implemented after the 2007 ESH/ESC hypertension guidelines, reporting the modalities of TOD assessment in hypertensive patients without an established cardiovascular or renal disease in Europe. This study provides a number of noteworthy findings. First, the three main recommended sets of subclinical TOD (LVH, peripheral vascular and renal) are commonly assessed and showed the highest effectiveness in upgrading cardiovascular risk. Importantly, however, a combined evaluation of LVH, vascular and renal TOD assessments was performed in only 63.2% of cardiologists’ and 49.5% of GPs’ patients. In addition, a retinopathy was also frequently searched for, whereas brain imaging was rare. Overall, less than 10% of patients had a quintuple evaluation of the full TOD spectrum. To which extent these results may influence cardiovascular prognosis of patients while not identifying high-risk patients who require a more intensive risk factor management warrants further investigation.

Indeed, our results showed a low reclassification of cardiovascular risk overall (only 3.3% of GPs’ patients and 15.4% of cardiologists’ patients were reclassified with an upgraded cardiovascular risk) associated with an increased number of TOD searches in both surveyed groups. Meanwhile, the costs obviously increased with the number of TOD searches, regardless of the association considered. In this setting, the usefulness of such costs appears questionable, considering the high number of hypertensive patients for whom a TOD assessment is currently recommended.

Second, the present survey reveals that the newly designated TOD assessment modalities emphasized by the latest ESH/ESC guidelines, namely PWV (3.4% of cardiologists’ patients, 0.8% of GPs’ patients), ABI (17.8% of cardiologists’ patients, 6.5% GPs’ patients), microalbuminuria (16.4% of cardiologists’ patients, 18.4% of GPs’ patients), are rarely used globally. Moreover, the above rates are much lower than that observed in an earlier European survey, in which 250 French physicians (GPs, cardiologists and diabetologists) were declared to assess 28.5% of their patients (not described in the latter study) for microalbuminuria [11]. It should be highlighted however that these latest modalities as well as carotid intima–media thickness are not currently recommended by French guidelines, and all but microalbuminuria (which may be investigated, however, in patients with a low or moderate cardiovascular risk according to the French guidelines [5]) are therefore not currently reimbursed by healthcare coverage, thereby limiting their implementation. Whether these new TOD modalities may allow a better risk reclassification certainly warrants further prospective studies, in association with an economic assessment. Third, blood pressure control was found to be rather poor when using office blood pressure measurement, although this hardly influenced TOD assessment modalities. The rate of blood pressure control observed herein was slightly lower than that reported in 2007 in France during an international survey [12]. Indeed, this latter survey led in France by 52 cardiologists and 201 GPs reported a SBP/DBP of 139/80 mmHg and blood pressure control (defined as a blood pressure level <140/90 mmHg) achieved in 46% of 3140 outpatients (mean age 66 years, 51% men, 17% with coronary artery disease, 9% with heart failure, 5% with cerebral ischemia, 9% with peripheral arterial disease, 18% with diabetes mellitus). Using the same definition in the present study, instead of a dichotomized definition with regard to diabetes, a blood pressure control rate of 32% in cardiologists’ patients and 39% in GPs’ patients was still observed.

Limitations

The study consisted in a visit-based survey, which likely oversamples sicker patients, who are more likely to visit physicians [12]. However, a representative sample of French private practice cardiologists and GPs was used, with the aim of studying their method of assessing TOD. In addition, office blood pressure measurements were considered as means of assessment, which may have underestimated the blood pressure control rate. However, the latter appeared to have little influence on TOD assessment. The sequence of TOD searches was not recorded in the present study. Whether certain evaluations may have been guided by some habits (e.g. vascular evaluations in smokers) was not assessed herein. Finally, no cost–benefit evaluation was feasible owing to the cross-sectional design of our study, and thus, the absence of cardiovascular outcome assessment and expense data, that is to which extent such upgraded cardiovascular risk, may have influenced patient care and outcomes.

In conclusion, subclinical TOD modalities are commonly assessed in French hypertensive patients without established cardiovascular or renal diseases; however, 40–50% patients still do not benefit from a combined triple assessment of LVH, macrovascular and renal TOD. Furthermore, the new guideline-recommended modalities of TOD assessment (PWV, ABI, microalbuminuria) as well as MRI or carotid intima–media thickness measurement remain very rarely implemented. In this setting, our study results highlight a poor effectiveness of TOD assessment for upgrading cardiovascular risk classification at a non-negligible cost. Thus, the cost–benefit effectiveness of TOD searches (including new modalities) to improve prediction of cardiovascular events in hypertensive patients without an established cardiovascular or renal disease should be assessed by dedicated prospective studies.

ACKNOWLEDGEMENTS

We thank Mr Pierre Pothier for editing of the manuscript.

Conflicts of interest

The study was granted by Astra-Zeneca. P.R., A.-I.T. and C.M.-V. received honoraria from Astra-Zeneca. A.T. is an Astra-Zeneca staff member.

Reviewers’ Summary Evaluations Reviewer 1

Evaluation of subclinical target organ damage is of paramount importance when it comes to evaluate global risk profile. Thus, a report on clinical attitudes and preferences of both GPs and cardiologists in France is an interesting and timely one. When looking at results, however, one must keep in mind that National French Recommendations differ slightly from ESH/ESC Guidelines (e.g. as for the usefulness of evaluating albuminuria). Furthermore, National Health System reimbursement regulations undoubtedly influence clinical practice. Results, indicating a disappointingly low prevalence of searches for microalbuminuria, must therefore be interpreted with caution. The finding that a relatively large fraction of patients do not seem to benefit from multiple assessments in term of cardiovascular risk stratification is an issue that needs to be investigated in greater detail.

Reviewer 2

This paper describes the habits of French cardiologists and general practitioners in assessing subclinical organ damage in hypertensive patients following 2007 ESH/ESC hypertension guidelines. It shows that only a limited percentage of patients have all major target organs assessed, while in the majority only one organ is evaluated, with preference to LVH, macrovascular and renal damge. The study underlines that French physicians rarely implement ESH/ESC recommendations for organ damage assessment, and in particular for routine search of microalbuminuria.

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Keywords:

cardiovascular risk classification; hypertension; target organ damage

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