Journal of Human Hypertension (2015) 29, 40–45 & 2015 Macmillan Publishers Limited All rights reserved 0950-9240/15 www.nature.com/jhh
ORIGINAL ARTICLE
Suitability of antiplatelet therapy in hypertensive patients MJ Martı´nez-Orozco1,2, Z Perseguer-Torregrosa2,3, VF Gil-Guille´n2, A Palazo´n-Bru2, D Orozco-Beltran2 and C Carratala´-Munuera2 Antiplatelet therapy (AT) is indicated in hypertensive patients with increased cardiovascular risk. The literature about the adequate or inadequate prescription of AT is scarce. We conducted a prospective descriptive study to quantify therapeutic inertia and nonguideline-recommended prescription (NGRP) of AT (aspirinor clopidogrel or both), and to assess associated factors, calculating the adjusted odds ratios (ORs) from multivariate models. In 2007–2009, 712 primary health-care hypertensive patients in a Spanish region were enrolled. Inertia was defined as the lack of an AT prescription, despite being indicated by guidelines, whereas NGRP was defined as AT prescription when there was no guideline recommendation. We also recorded cardiovascular variables. Inertia and NGRP were quantified for primary and secondary prevention. Of 108 patients in secondary prevention, 53 had inertia (49.1%, 95% confidence interval (CI): 39.6–58.5%). Associated profile: female (OR ¼ 0.460, P ¼ 0.091), no dyslipidemia (OR ¼ 0.393, P ¼ 0.048), no coronary heart disease (OR ¼ 0.215, P ¼ 0.001) and high diastolic blood pressure (OR ¼ 1.076, P ¼ 0.016). In primary prevention, NGRP was present in 69 of 595 patients (11.6%, 95% CI: 9.0–14.2%). Associated profile: male (OR ¼ 1.610, P ¼ 0.089), smoking (OR ¼ 2.055, P ¼ 0.045), dyslipidemia (OR ¼ 3.227, Po0.001) and diabetes (OR ¼ 2.795, Po0.001). Although certain factors were clearly associated with these phenomena much still remains to be learnt. Journal of Human Hypertension (2015) 29, 40–45; doi:10.1038/jhh.2014.25; published online 3 April 2014
INTRODUCTION Improving adequate prescription practices for treatment requires that clinicians accept and adopt clinical practice guidelines previously agreed by national and international experts. The two main factors preventing achievement of the objectives concerning disease control (hypertension, diabetes, dyslipidemia, and so on) are lack of compliance and therapeutic inertia.1 This latter concept was defined by Phillips as failure to initiate or intensify treatment by physicians when indicated.2 According to the Interdisciplinary Spanish Committee for Cardiovascular Prevention (CEIPC), antiplatelet therapy (AT) is indicated in the primary prevention of hypertensive patients when their cardiovascular risk, as measured with the SCORE, is X10%; in secondary prevention AT should be prescribed systematically. Aspirin is usually prescribed, although in patients who are allergic to aspirin clopidogrel is normal. Clopidogrel is prescribed in addition to aspirin for at least 1 month in patients who have had an acute coronary syndrome, in revascularized patients with implantation of a coated stent, or for at least 12 months in patients with a non-ST elevation acute coronary syndrome. No recommendation exists for the systematic combination of both agents in patients with chronic stable atherosclerotic disease.3 The incidence of therapeutic inertia is very high in patients with hypertension and is strongly associated with good blood pressure control, reaching 80% in clinical practice.4,5 Just as important as the concept of inertia is excess treatment in the form of nonguideline-recommended prescription (NGRP). With this, patients can suffer undesired adverse secondary events, particularly hemorrhage in the case of AT. Controversy exists regarding the indications for AT in primary prevention, as is the case, for example, with diabetic patients or patients with a low-risk threshold, as well as in secondary prevention in various cardiovascular diseases, like kidney failure.
The evidence so far does not clarify the recommendations concerning AT.6–10 We are unaware of any study evaluating simultaneously both the adequate and the inadequate prescription of AT in the prevention of cardiovascular disease. Accordingly, we conducted a study in the primary care setting to determine whether hypertensive patients are or are not prescribed suitable AT, analyzing the excess or deficiency of therapy according to the guidelines, as well as associated factors. MATERIALS AND METHODS Study population This study was performed in the Valencian Community, which is a Mediterranean region in eastern Spain. The health system has universal coverage and primary care is freely accessible. The main characteristics of patients attending primary care services are predominantly women, coexistence of cardiovascular risk factors, older age and high frequentation. The physicians are all aware of the medical guidelines for clinical practice.11
Design and participants We undertook a descriptive prospective observational study evaluating at three visits whether a hypertensive patient was taking AT (aspirin or clopidogrel or both). The indication for therapy was always by prescription, not by self-medication of the patients. The visits were undertaken 1 month and 2 months after the first visit. The visits took place at 20 health centers and one community pharmacy in the Valencian Community. The data collection started on 26 March 2007 and finished on 14 August 2009. We invited 767 hypertensive patients to participate. They were recruited consecutively at health centers when they went to see their physician to obtain prescriptions and at the pharmacy when they attended to collect their prescribed medication. The following selection criteria were defined: (a) inclusion: hypertensive patient aged 25 years or older, on antihypertensive treatment for at least
1 Miguel Martı´nez Community Pharmacy, Benimantell, Spain; 2Department of Clinical Medicine, Miguel Herna´ndez University, San Juan de Alicante, Spain and 3Zeneida Perseguer Community Pharmacy, Petrel, Spain. Correspondence: Professor A Palazo´n-Bru, Department of Clinical Medicine, Miguel Herna´ndez University, Carretera de Valencia-Alicante S/N San Juan de Alicante, Alicante 03550, Spain. E-mail: [email protected] Received 24 August 2013; revised 14 February 2014; accepted 18 February 2014; published online 3 April 2014
Antiplatelet therapy inertia in hypertension MJ Martı´nez-Orozco et al
41 3 months and who agreed to participate in the study. (b) Exclusion: patient refusal to participate in the study, severe concomitant disorders or conditions that the physician or the pharmacist considered could mask the results, any factor related to mental, pathological or social disorders considered by the researcher to hinder or prevent the follow-up, pregnant or lactating women, hypertensive patients involved in another study, hypertensive patients who lived in the same house as somebody else taking the same antihypertensive treatment, hypertensive patients who had no contact phone number to call in the event that they failed to attend, hypertensive patients obtaining their treatment at different pharmacies (this only for the patients at the pharmacy), hypertensive patients for whom it was not possible to determine whether they had taken the AT during the follow-up (the patients were asked to bring their aspirin or clopidogrel packet with them in order to have two quality criteria to determine the taking or not taking of the AT: the office record and the checking of the packets (this only for the patients at the pharmacy)). Of the 767 patients invited to participate, 712 finally finished the study, representing a loss rate of 7.2%, of which 1.7% (n ¼ 13) had one or more exclusion criteria and 5.5% (n ¼ 42) withdrew from the study.
Variables and measurements The principal parameters measured were: Therapeutic inertia if the patient on secondary prevention or primary
prevention with a CEIPC SCORE X10%3 was not prescribed AT by the physician. At the pharmacy, this was assessed after checking the packets brought to the pharmacy by the patient, telephone consultation with the physician and seeing the computerized record of the office. This parameter was measured separately for primary and secondary prevention. Excess antiplatelet prescription in patients who received a prescription despite it not being recommended according to the CEIPC.3 Obviously, this parameter was performed only for primary prevention, because all patients in secondary prevention have the recommendation for AT. Furthermore, the following variables associated with hypertension, according to the European consensus hypertension guidelines,12 were measured: gender, smoking, dyslipidemia, diabetes, personal history of cardiovascular disease (defined by European Society of Hypertension/ European Society of Cardiology guidelines12 or coronary heart disease or stroke, number of drugs for high blood pressure, systolic and diastolic blood pressure, and age; the body mass index was also calculated. In addition, we performed measurements of total cholesterol and highdensity lipoprotein cholesterol to calculate the cardiovascular risk (CEIPC SCORE3 in primary prevention patients. Data on gender, smoking habits, personal history of disease, number of drugs for high blood pressure and age were obtained during the patient interview and corroborated from the clinical records. The blood pressure was measured at each visit taking two measurements, according to the 2007 European guidelines12 with a validated and calibrated automated forearm oscillometric sphygmomanometer (Omron CPII 705, Omron, Kyoto, Japan). The body mass index was calculated using the standard methods to measure weight and height. To obtain the lipid parameters, blood was drawn at the start of the morning after an 8-h fast using calibrated devices. The cardiovascular risk was calculated from the CEIPC SCORE,3 which uses calculations of both total cholesterol and the ratio of total cholesterol to high-density lipoprotein cholesterol; the highest value was used in both cases. At the first visit, the patients were informed about the study and we assessed their exclusion criteria. In addition, the following variables were measured: anthropometric data, smoking habit, the presence of diabetes mellitus and dyslipidemia, a history of cardiovascular disease and the blood pressure. At the second visit, we asked the patients about their drugs and the blood pressure was measured. Finally, at the last visit the drugs and the blood pressure were assessed and we performed the blood tests.
Sample size Of the 712 hypertensive patients analyzed, 108 patients in secondary prevention should have had a recommendation for AT, but 53 of these had inertia. Nine patients in primary prevention should have had the recommendation and all had inertia; because of the small sample size, no further analysis was done in this group. The other 595 patients in & 2015 Macmillan Publishers Limited
primary prevention should have had no recommendation for AT, although 69 of them had a NGRP. Thus, using a 95% confidence level and a maximum expected ratio (P ¼ q ¼ 0.5), the expected error rate in the estimations of inertia in secondary prevention and NGRP in primary prevention were 9.4% and 4.0%, respectively.
Statistical methods The qualitative variables are expressed as exact amounts and percentages and the quantitative variables as mean and standard deviation. A multivariable logistic regression model was performed to estimate adjusted odds ratios (ORs) for relationships between the principal parameters and the study variables. In secondary prevention patients, because of the fact that we had few patients and few events (therapeutic inertia), we selected fewer variables to have a n:k ratio (number of events/number of predictors in the model) greater than 10 (a total of 5 variables in our case, 53/5 ¼ 10.6). The selection strategy performed was: (a) to compare percentages or means of the explanatory variables between having and not having inertia using the w2-tests (Pearson and Fisher) and Student’s t-test, (b) sort the variables according to the P-values obtained (low to high) and (c) select the top 5. Accordingly, in this group of patients, we adjusted the ORs for the chosen variables using the previous strategy. For the patients in primary prevention, there were not enough patients or events (NGRP) to use all the study variables in the model. We therefore adjusted the ORs for gender, smoking, dyslipidemia, diabetes, number of drugs for high blood pressure, systolic blood pressure, diastolic blood pressure, age and body mass index. The lipid parameters were not included in the adjustment because of their collinearity with dyslipidemia. The likelihood ratio test was carried out for the goodness-of-fit of the model. Furthermore, we compared the patients who completed the study with those who withdrew from it, using tests based on the w2 (Pearson and Fisher tests) and Student’s t-test. All analyses were performed at a 5% significance level and associated confidence intervals (CIs) were estimated for each relevant parameter. The statistical analysis was done using IBM SPSS Statistics 19.0 (IBM, Armonk, NY, USA).
Ethical consideration The study afforded no extra risk to the patient and an indirect benefit was expected as the results would improve the use of AT in the primary healthcare setting. The study was conducted according to the principles of the World Medical Association Declaration of Helsinki13 and complied with the norms in the European Union guidelines of good clinical practice. Each patient was informed about the study and the data required, and promised to attend the three visits and do the tests involved. This was done at the first visit where the patient provided signed consent. The study was approved by the Ethics Committee of the Health Department of Elda (Valencian Community).
RESULTS Figure 1 shows the number of patients in each study phase. Of 767 patients invited to participate, 754 were finally included in the study. Of these, 712 completed all three visits and 42 did not. The reasons for withdrawal at the first visit (n ¼ 30) were death (2), wish to cease taking the medication (1), personal reasons (10), not answering the telephone (1), hospital admission (3), pain while taking the blood pressure (2), not bringing the medication in an organized way (1) and unknown (10). The reasons for withdrawal at the second visit (n ¼ 12) were hospital admission (1), change in medication (3), not bringing the prescribed medicine (4), personal reasons (3) and unknown (1). Of the 712 study patients, 117 had a guideline recommendation for AT (7.7%, primary prevention; 92.3%, secondary prevention) and 595 did not. The descriptive characteristics of the study sample (n ¼ 712) are summarized in Table 1. Those patients who completed the study had a high prevalence of cardiovascular risk factors (smoking 16%, dyslipidemia 44.7% and diabetes 23.3%); additionally, about 15% of them were in secondary prevention, they had an advanced age (mean of 63.6 years), and their mean body mass index was greater than 30 kg m 2 (30.3). Regarding comparison of the patients who completed the study with those who withdrew from it, the Journal of Human Hypertension (2015) 40 – 45
Antiplatelet therapy inertia in hypertension MJ Martı´nez-Orozco et al
42
Figure 1.
Hypertensive patients who participated in the study at primary health care in the Valencian Community (Spain), 2007–2009 data.
Table 1.
Descriptive analysis for hypertensive patients who completed or withdrew from the study at primary health care in the Valencian Community (Spain), 2007–2009 data Variable
Antiplatelet therapya Aspirin Clopidogrel Both None Male gender Smoking Dyslipidemia Diabetes Secondary prevention CHD Stroke CEIPC SCORE X10%b Number of drugs for high blood pressurea SBP (mmHg)c DBP (mmHg)c Age (years) BMI (kg m 2) Total cholesterol (mmol l 1)b HDL cholesterol (mmol l 1)b
Completed the study n ¼ 712, n (%)/x (s.d.)
Withdrew from the study n ¼ 42, n (%)/x (s.d.)
Pvalue
103 16 5 588 315 114 318 166 108 44 19 9 2.5
(14.5) (2.2) (0.7) (82.6) (44.2) (16.0) (44.7) (23.3) (15.2) (6.2) (2.7) (1.5) (2.5)
2 (16.7) 0 (0) 0 (0) 10 (83.3) 20 (47.6) 10 (23.8) 14 (33.3) 16 (38.1) 12 (28.6) 1 (2.4) 1 (2.4) NA 1.8 (1.2)
0.674 0.185 0.151 0.030 0.021 0.505 1 NA 0.050
139.6 80.7 63.6 30.3 4.9 1.5
(18.4) (9.8) (11.7) (5.0) ( 0.9) (0.4)
143.5 (19.2) 78.3 (12.6) 67.0 (9.4) 32.2 (6.2) NA NA
0.181 0.235 0.067 0.028 NA NA
0.788
Abbreviations: BMI, body mass index; CEIPC, Interdisciplinary Spanish Committee for Cardiovascular Prevention; CHD, coronary heart disease; DBP, diastolic blood pressure; HDL, high-density lipoprotein; n (%), absolute frequency (relative frequency); NA, not applicable; SBP, systolic blood pressure; x (s.d.), mean (s.d.). aOnly in patients with two or three visits bOnly in patients with primary prevention and three visits. cThe blood pressure mean was calculated using all the patient visits in the study (three visits if they completed the study, one or two visits if they withdrew from the study). The lipids and the CEIPC SCORE do not appear for patients who withdrew from the study because these parameters were measured at the last visit.
Journal of Human Hypertension (2015) 40 – 45
patients who withdrew from the study were significantly (Po0.05) more likely to have diabetes, be in secondary prevention, and have a higher body mass index than those who completed the study. Finally, concerning the antiplatelet medication, we did not find any differences between the two groups. Therapeutic inertia could only be evaluated in secondary prevention (n ¼ 108) and its magnitude was 49.1% (95% CI: 39.6–58.5%). Concerning the type of AT prescribed in those patients who did not experience therapeutic inertia, we found that the most prescribed drug was aspirin (Table 2). In the analysis of factors associated with therapeutic inertia (Table 2), the chosen variables with their P-values in the strategy were: coronary heart disease (o0.001), diastolic blood pressure (0.004), dyslipidemia (0.006), systolic blood pressure (0.076) and gender (0.178). The other P-values (not included in the regression model) were: stroke, 0.240; diabetes, 0.447; smoking, 0.618; body mass index, 0.628; number of drugs for high blood pressure, 0.760; age, 0.815. The logistic regression model showed that the factors associated with higher inertia were being a woman (OR ¼ 0.460, 95% CI: 0.187– 1.133, P ¼ 0.091), no dyslipidemia (OR ¼ 0.393, 95% CI: 0.156– 0.992, P ¼ 0.048), no coronary heart disease (OR ¼ 0.215, 95% CI: 0.086–0.539, P ¼ 0.001), low systolic blood pressure (OR ¼ 0.993, 95% CI: 0.959–1.027, P ¼ 0.667) and high diastolic blood pressure (OR ¼ 1.076, 95% CI: 1.014–1.142, P ¼ 0.016). NGRP was present in 69 of 595 patients (11.6%, 95% CI: 9.0–14.2%). By definition, this was only evaluated in primary prevention, as all patients in secondary prevention are recommended to receive AT. The AT used for the patients with a NGRP was aspirin (62), clopidogrel (4) and both (3; Table 3). Furthermore, Table 3 summarizes the factors that were associated with NGRP. Themost relevant were: gender male (OR ¼ 1.610, 95% CI: 0.930–2.786, P ¼ 0.089), smoking (OR ¼ 2.055, 95% CI: 1.017– 4.152, P ¼ 0.045), dyslipidemia (OR ¼ 3.227, 95% CI: 1.860–5.599, Po0.001) and diabetes (OR ¼ 2.795, 95% CI: 1.604–4.871, & 2015 Macmillan Publishers Limited
Antiplatelet therapy inertia in hypertension MJ Martı´nez-Orozco et al
43 Table 2. Analysis of the inertia for antiplatelet therapy for hypertensive patients in secondary prevention at primary health care in the Valencian Community (Spain), 2007–2009 data Variable
Antiplatelet therapy recommended by guidelines n ¼ 108 n (%)/x (s.d.)
Inertia n ¼ 53 (49.1%) n (%)/x (s.d.)
Adj. OR
95% CI (Adj. OR)
P-value
Antiplatelet therapy Aspirin Clopidogrel Both None
41 12 2 53
Gender Male Femalea
54 (50.0) 54 (50.0)
23 (42.6) 30 (55.6)
0.460
(0.187, 1.133)
0.091
Smokingb Yes No
14 (13.0) 94 (87.0)
6 (42.9) 47 (50.0)
Dyslipidemia Yes Noa
69 (63.9) 39 (36.1)
27 (39.1) 26 (66.7)
0.393
(0.156, 0.992)
0.048
Diabetesb Yes Noa
31 (28.7) 77 (71.3)
17 (54.8) 36 (46.8)
CHD Yes Noa
44 (40.7) 64 (59.3)
12 (27.3) 41 (64.1)
0.215
(0.086, 0.539)
0.001
0.993 1.076
(0.959, 1.027) (1.014, 1.142)
0.667 0.016
Strokeb Yes No Number of drugs for high blood pressureb SBP (mm Hg) DBP (mm Hg) Age (years)b BMI (kg m 2)b
19 89 3.1 135.4 76.4 68.2 29.3
(38.0) (11.1) (1.9) (49.1)
(17.6) (82.4) (2.5) (15.1) (8.9) (8.8) (4.2)
7 (36.8) 46 (51.7) 3.0 (2.5) 138.1(14.5) 78.9 (9.1) 68.0 (8.6) 29.5 (4.3)
Abbreviations: Adj. OR, adjusted odds ratio; BMI, body mass index; CHD, coronary heart disease; CI, confidence interval; DBP, diastolic blood pressure; n(%), absolute frequency (relative frequency); SBP, systolic blood pressure; x(s.d.), mean (s.d.). Likelihood ratio test: w2 ¼ 28.8, Po0.001. OR adjusted for gender, dyslipidemia, CHD, SBP and DBP. aReference. bNot included in the model (see strategy in statistical methods).
Po0.001). None of the other factors was in the least significant (P40.10): higher number of drugs for high blood pressure (OR ¼ 1.031, 95% CI: 0.934–1.138, P ¼ 0.546), higher systolic blood pressure (OR ¼ 1.010, 95% CI: 0.997–1.022, P ¼ 0.130), lower diastolic blood pressure (OR ¼ 0.979, 95% CI: 0.950–1.009, P ¼ 0.169), older age (OR ¼ 1.010, 95% CI: 0.985–1.035, P ¼ 0.429) and higher body mass index (OR ¼ 1.013, 95% CI: 0.959–1.071, P ¼ 0.637). DISCUSSION The patients who withdrew from the study had an increased cardiovascular risk (diabetes, secondary prevention and higher body mass index) as compared with those who remained in the study. As this study was not a clinical trial, this did not represent a selection bias as our objective was to quantify a problem, but not to compare different groups. This study highlights the important degree of therapeutic inertia and NGRP in AT in hypertensive patients. However, because of the very few studies along the same lines, we can only compare our results in such conditions as hypertension and diabetes. Critical review of these studies shows great variability, with 70–85% of poorly controlled patients whose physicians adopt a conservative attitude and prefer not to change the treatment.14–17 Nevertheless, when the study is undertaken among motivated physicians who are aware of the concept of therapeutic inertia, the magnitude of the problem is greatly reduced, with prevalence rates of therapeutic inertia around 33%.16 The lack of similar & 2015 Macmillan Publishers Limited
studies to ours, although, prevents comparison of the magnitude found here, but committing therapeutic inertia in one out of every two hypertensive patients who need AT and the NGRP of AT in one out of every nine patients warrants reflection about changing clinical practice. Consideration should be given to possible episodes of hemorrhage, particularly in patients treated with AT and high blood pressure. The analysis of the factors predicting therapeutic inertia and NGRP reflects the current controversies concerning the indications for AT in hypertensive patients, particularly in primary prevention.8,9,18–20 The results were encouraging in that the patients who were better controlled with AT were precisely those who most needed it, that is, hypertensive patients who had had a coronary heart disease. It should not be forgotten, although, that an important percentage of hypertensive patients with these conditions were not receiving AT. Concerning risk factors, the dyslipidemic patients presented better indices of AT. Nevertheless, these factors should be corroborated with other studies involving a larger sample. The finding of greater NGRP of AT in dyslipidemic and diabetic hypertensive patients could reflect the current controversies about whether these patients should or should not receive AT and the low measurement of cardiovascular risk in these hypertensive patients. The multivariate models only used patient variables, so other factors may influence our indicators; for example, variables associated with the physician–patient relationship, physician training or work setting. Journal of Human Hypertension (2015) 40 – 45
Antiplatelet therapy inertia in hypertension MJ Martı´nez-Orozco et al
44 Table 3. Analysis of the NGRP of antiplatelet therapy for hypertensive patients in primary prevention at primary health care in the Valencian Community (Spain), 2007–2009 data Variable
Antiplatelet therapy not recommended by guidelines n ¼ 595 n (%)/x (s.d.)
NGRP, n ¼ 69 (11.6%) n (%)/x (s.d.)
Adj. OR
95% CI (Adj. OR)
P-value
Antiplatelet therapy Aspirin Clopidogrel Both None
62 4 3 526
Gender Male Femalea
252 (42.4) 342 (57.5)
38 (15.1) 31 (9.1)
1.610
(0.930, 2.786)
0.089
Smoking Yes Noa
91 (15.3) 504 (84.7)
15 (16.5) 54 (10.7)
2.055
(1.017, 4.152)
0.045
Dyslipidemia Yes Noa
246 (41.3) 349 (48.7)
46 (18.7) 23 (6.6)
3.227
(1.860, 5.599)
o0.001
2.795
(1.604, 4.871)
o0.001
1.031 1.010 0.979 1.010 1.013
(0.934, 1.138) (0.997, 1.022) (0.950, 1.009) (0.985, 1.035) (0.959, 1.071)
0.546 0.130 0.169 0.429 0.637
Diabetes Yes Noa Number of drugs for high blood pressure SBP (mmHg) DBP (mmHg) Age (years) BMI (kg m 2) Total cholesterol (mmol l 1) HDL cholesterol (mmol l 1)
133 462 2.5 140.0 81.4 62.8 30.6 4.9 1.5
(10.4) (0.7) (0.5) (88.4)
(22.4) (77.6) (2.5) (18.8) (9.8) (12.0) (5.2) (0.9) (0.4)
62 4 3 0
30 39 2.9 142.1 80.2 64.0 30.8 4.7 1.5
(89.9) (5.8) (4.3) (0.0)
(22.6) (8.4) (3.1) (16.2) (10.9) (14.3) (4.5) (1.1) (0.4)
Abbreviations: Adj. OR, adjusted odds ratio; BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; HDL, high-density lipoprotein; n(%), absolute frequency (relative frequency); NGRP, non-guideline-recommended prescription; SBP, systolic blood pressure; x (s.d.), mean (s.d.). Likelihood ratio test: w2 ¼ 46.9, Po0.001. OR adjusted by gender, smoking, dyslipidemia, diabetes, number of drugs for high blood pressure, SBP, DBP, age and BMI. Lipid parameters not included in the multivariate model due to collinearity with dyslipidemia. aReference.
The importance of our study relates to the lack of other studies that have evaluated jointly the suitability of guidelinerecommended AT, that is, no treatment when indicated or giving treatment when not indicated. This is important because of the strong association and degree of evidence in certain hypertensive patients of the benefits of adequate AT20–23 and the excess risk of hemorrhage in patients receiving AT when it is not indicated.24,25 In clinical practice, being aware of the magnitude of therapeutic inertia and its associated factors is of particular relevance in order to establish strategies to change the situation. We attempted to minimize any possible weakness of the study by using very strict inclusion, exclusion and withdrawal criteria for patient selection in order to provide the best information possible. In addition, we were also very strict when measuring the main variables, as can be seen in the Materials and methods section. Notwithstanding all these precautions, the main limitation was the lack of statistical power in the subgroup analysis. For example, there were only nine patients receiving primary prevention with a SCORE X10% and we could not perform a multivariate analysis with more explanatory variables in the secondary prevention patients. We could not therefore analyze exhaustively the inertia in these subgroups of patients. A larger sample size could possibly have allowed the analysis of these relevant subgroups, considering the poor evaluation of cardiovascular risk and its frequent underestimation, especially in primary prevention.26,27 The indication for AT in secondary prevention is clearer.28 Emphasis should be given to the fact that, even assuming a minimum risk threshold, evidence now exists for the favorable effect of AT in primary prevention. The meta-analysis in the study by Raju et al.21 in the general population and the Fremantle study29 in diabetic patients highlights the benefit of aspirin in Journal of Human Hypertension (2015) 40 – 45
primary prevention. On the other hand, consideration should also be given to the risk of bleeding in the event of inadequate prescription and a balance made when deciding the risk/benefit ratio, as recommended by the various scientific societies.22,30 CONCLUSION In conclusion, in the use of AT to prevent events, both inertia and unsuitable prescription were relatively high. Although certain factors were clearly associated with these phenomena, much still remains to be learnt. As Cocheri recently said in a paper about AT in primary prevention ‘the game is not over’.31
What is known about topic Improving adequate prescription practices for treatment requires that clinicians accept and adopt clinical practice guidelines. The two main factors preventing achievement of the objectives are lack of compliance and therapeutic inertia. Antiplatelet therapy is indicated in hypertensive patients when they have high cardiovascular risk. Just as important as the concept of inertia is excess treatment in the form of prescription of non-guideline-recommended drugs. What this study adds We are unaware of any study evaluating simultaneously both the adequate and the inadequate prescription of antiplatelet therapy in hypertensive patients. As a new feature, we quantify whether hypertensive patients are or are not prescribed suitable antiplatelet therapy, analyzing the excess or deficiency of therapy according to the guidelines.
& 2015 Macmillan Publishers Limited
Antiplatelet therapy inertia in hypertension MJ Martı´nez-Orozco et al
45 CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank everyone who has contributed to the scientific content of the manuscript or provided technical support is in this section. We also thank the Conselleria de Sanitat (Valencian Community) for allowing us to use the equipment of the health centers and the computerized health system. We also thank Armina Sepehri for collaboration in the data computerization process, and Ian Johnstone for help with the English language version of the text. A research grant from the Department of Clinical Medicine at Miguel Herna´ndez University was used to buy reagents for biochemical testing. This was the only role of the funding sources in the study.
REFERENCES 1 Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals. Hypertension 2006; 47(3): 345–351. 2 Phillips LS, Branch WT, Cook CB, Doyle JP, El-Kebbi IM, Gallina DL et al. Clinical inertia. Ann Intern Med 2001; 135(9): 825–834, Review. 3 Lobos JM, Royo-Bordonada MA, Brotons C, Alvarez-Sala L, Armario P, Maiques A et al. Guı´a europea de prevencio´n cardiovascular en la pra´cticaclı´nica. Adaptacio´n Espan˜ola del CEIPC 2008. Rev Clin Esp 2009; 209(6): 279–302. 4 Marquez Contreras E, Martı´n de Pablos JL, Gil Guille´n V, Martel Claros N, Motero Carrasco J, Casado Martı´nez JJ. La inerciaclı´nicaprofesional y el incumplimientofarmacolo´gico +Co´moinfluyen en el control de la HTA? Estudio CUMAMPA. Hipertensio´n 2008; 25(5): 187–193. 5 Alonso Moreno FJ, Llisterri Caro JL, Rodrı´guez Roca GC, FerreiroMaduen˜o M, Gonza´lez-Segura Alsina D, Diviso´nGarrote JA et al. Conducta del me´dico de atencio´nprimaria ante el mal control de los pacienteshipertensos. Estudio PRESCAP 2006. Rev Clin Esp 2008; 208(8): 393–399. 6 Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008; 337: a1840. 7 Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008; 300(18): 2134–2141. 8 Antithrombotic Trialists’ (ATT) CollaborationBaigent C, Blackwell L, Collins R, Emberson J, Godwin J et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet 2009; 373(9678): 1849–1860. 9 De Berardis G, Sacco M, Strippoli GF, Pellegrini F, Graziano G, Tognoni G et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomized controlled trials. BMJ 2009; 339: b4531. 10 Fowkes FG, Price JF, Stewart MC, Butcher I, Leng GC, Pell AC et al. Aspirin for Asymptomatic Atherosclerosis Trialists. Aspirin for prevention of cardiovascular events in general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 2010; 303(9): 841–848. 11 PedreraCarbonell V, Gil Guille´n V, Orozco Beltra´n D, PrietoErades I, Schwarz Chavarri G, MoyaGarcı´a I. Caracterı´sticas de la demanda sanitaria en lasconsultas de medicina de familia de un a´rea de salud de la ComunidadValenciana. AtenPrimaria 2005; 35(2): 82–88. 12 Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G et al. 2007 Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25(6): 1105–1187.
& 2015 Macmillan Publishers Limited
13 World Medical Association Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. JAMA 1997; 277(11): 925–926. 14 Viera AJ, Schmid D, Bostrom S, Yow A, Lawrence W, DuBard CA. Level of blood pressure above goal and clinical inertia in a Medicaid population. J Am Soc Hypertens 2010; 4(5): 244–254. 15 Redo´n J, Coca A, La´zaro P, Aguilar MD, Caban˜as M, Gil N et al. Factors associated with therapeutic inertia in hypertension: validation of a predictive model. J Hypertens 2010; 28(8): 1770–1777. 16 Gil-Guille´n V, Orozco-Beltra´n D, Pe´rez RP, Alfonso JL, Redo´n J, Pertusa-Martı´nez S et al. Clinicalinertia in diagnosis and treatment of hypertension in primary care: quantification and associated factors. Blood Press 2010; 19(1): 3–10. 17 Harris SB, Kapor J, Lank CN, Willan AR, Houston T. Clinical inertia in patients with T2DM requiring insulin in family practice. Can Fam Physician 2010; 56(12): e418–e424. 18 US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2009; 150(6): 396–404. 19 Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006; 295(17): 306–3132002. 20 Gkaliagkousi E, Passacquale G, Douma S, Zamboulis C, Ferro A. Platelet activation in essential hypertension: implications for antiplatelet treatment. Am J Hypertens 2010; 23(3): 229–236. 21 Raju N, Sobieraj-Teague M, Hirsh J, O’Donnell M, Eikelboom J. Effect of aspirin on mortality in the primary prevention of cardiovascular disease. Am J Med 2011; 124(7): 621–629. 22 Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R et al. European guidelines oncardiovascular disease prevention in clinical practice: full text. Fourth JointTask Force of the European Society of Cardiology and other societies oncardiovascular disease prevention in clinical practice (constituted byrepresentatives of nine societies and by invited experts). Eur J Cardiovasc Prev Rehabil 2007; 14(Suppl 2): S1–113. 23 Berger JS, Lala A, Krantz MJ, Baker GS, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: a metaanalysis of randomized trials. Am Heart J 2011162 1(115-24): e2. 24 Weil J, Colin-Jones D, Langman M, Lawson D, Logan R, Murphy M et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 1995; 310(6983): 827–830. 25 Yeomans ND, Lanas AI, Talley NJ, Thomson AB, Daneshjoo R, Eriksson B et al. Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin. Aliment Pharmacol Ther 2005; 22(9): 795–801. 26 Ma´rquez-Contreras E, De Rivas-Otero B, Diviso´n JA, SobrevielaBla´zquez E, Luque Otero M. Evaluamos y controlamosadecuadamente a los hipertensosatendidos en Atencio´nPrimaria? Estudio HICAP. An Med Interna 2007; 24(7): 312–316. 27 Marquez-Contreras E, Coca A, de la Figuera-vonWichmann E, Diviso´n JA, Llisterri JL, Sobrino J et al. Perfil de riesgo cardiovascular de los pacientes con hypertension arterial no controlada. Estudio Control-Project. Med Clin (Barc) 2007; 128(3): 86–91. 28 Antithrombotic Trialist Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients. BMJ 2002; 324(7330): 71–86. 29 Ong G, Davis TM, Davis WA. Aspirin is associated with reduced cardiovascular and all-cause mortality in type 2 diabetes in a primary prevention setting: the Fremantle Diabetes study. Diabetes Care 2010; 33(2): 317–321. 30 Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27(11): 2121–2158. 31 Coccheri S. Antiplatelet therapy: controversial aspects. Thromb Res 2012; 129(3): 225–229.
Journal of Human Hypertension (2015) 40 – 45
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ORIGINAL ARTICLE
Suitability of antiplatelet therapy in hypertensive patients MJ Martı´nez-Orozco1,2, Z Perseguer-Torregrosa2,3, VF Gil-Guille´n2, A Palazo´n-Bru2, D Orozco-Beltran2 and C Carratala´-Munuera2 Antiplatelet therapy (AT) is indicated in hypertensive patients with increased cardiovascular risk. The literature about the adequate or inadequate prescription of AT is scarce. We conducted a prospective descriptive study to quantify therapeutic inertia and nonguideline-recommended prescription (NGRP) of AT (aspirinor clopidogrel or both), and to assess associated factors, calculating the adjusted odds ratios (ORs) from multivariate models. In 2007–2009, 712 primary health-care hypertensive patients in a Spanish region were enrolled. Inertia was defined as the lack of an AT prescription, despite being indicated by guidelines, whereas NGRP was defined as AT prescription when there was no guideline recommendation. We also recorded cardiovascular variables. Inertia and NGRP were quantified for primary and secondary prevention. Of 108 patients in secondary prevention, 53 had inertia (49.1%, 95% confidence interval (CI): 39.6–58.5%). Associated profile: female (OR ¼ 0.460, P ¼ 0.091), no dyslipidemia (OR ¼ 0.393, P ¼ 0.048), no coronary heart disease (OR ¼ 0.215, P ¼ 0.001) and high diastolic blood pressure (OR ¼ 1.076, P ¼ 0.016). In primary prevention, NGRP was present in 69 of 595 patients (11.6%, 95% CI: 9.0–14.2%). Associated profile: male (OR ¼ 1.610, P ¼ 0.089), smoking (OR ¼ 2.055, P ¼ 0.045), dyslipidemia (OR ¼ 3.227, Po0.001) and diabetes (OR ¼ 2.795, Po0.001). Although certain factors were clearly associated with these phenomena much still remains to be learnt. Journal of Human Hypertension (2015) 29, 40–45; doi:10.1038/jhh.2014.25; published online 3 April 2014
INTRODUCTION Improving adequate prescription practices for treatment requires that clinicians accept and adopt clinical practice guidelines previously agreed by national and international experts. The two main factors preventing achievement of the objectives concerning disease control (hypertension, diabetes, dyslipidemia, and so on) are lack of compliance and therapeutic inertia.1 This latter concept was defined by Phillips as failure to initiate or intensify treatment by physicians when indicated.2 According to the Interdisciplinary Spanish Committee for Cardiovascular Prevention (CEIPC), antiplatelet therapy (AT) is indicated in the primary prevention of hypertensive patients when their cardiovascular risk, as measured with the SCORE, is X10%; in secondary prevention AT should be prescribed systematically. Aspirin is usually prescribed, although in patients who are allergic to aspirin clopidogrel is normal. Clopidogrel is prescribed in addition to aspirin for at least 1 month in patients who have had an acute coronary syndrome, in revascularized patients with implantation of a coated stent, or for at least 12 months in patients with a non-ST elevation acute coronary syndrome. No recommendation exists for the systematic combination of both agents in patients with chronic stable atherosclerotic disease.3 The incidence of therapeutic inertia is very high in patients with hypertension and is strongly associated with good blood pressure control, reaching 80% in clinical practice.4,5 Just as important as the concept of inertia is excess treatment in the form of nonguideline-recommended prescription (NGRP). With this, patients can suffer undesired adverse secondary events, particularly hemorrhage in the case of AT. Controversy exists regarding the indications for AT in primary prevention, as is the case, for example, with diabetic patients or patients with a low-risk threshold, as well as in secondary prevention in various cardiovascular diseases, like kidney failure.
The evidence so far does not clarify the recommendations concerning AT.6–10 We are unaware of any study evaluating simultaneously both the adequate and the inadequate prescription of AT in the prevention of cardiovascular disease. Accordingly, we conducted a study in the primary care setting to determine whether hypertensive patients are or are not prescribed suitable AT, analyzing the excess or deficiency of therapy according to the guidelines, as well as associated factors. MATERIALS AND METHODS Study population This study was performed in the Valencian Community, which is a Mediterranean region in eastern Spain. The health system has universal coverage and primary care is freely accessible. The main characteristics of patients attending primary care services are predominantly women, coexistence of cardiovascular risk factors, older age and high frequentation. The physicians are all aware of the medical guidelines for clinical practice.11
Design and participants We undertook a descriptive prospective observational study evaluating at three visits whether a hypertensive patient was taking AT (aspirin or clopidogrel or both). The indication for therapy was always by prescription, not by self-medication of the patients. The visits were undertaken 1 month and 2 months after the first visit. The visits took place at 20 health centers and one community pharmacy in the Valencian Community. The data collection started on 26 March 2007 and finished on 14 August 2009. We invited 767 hypertensive patients to participate. They were recruited consecutively at health centers when they went to see their physician to obtain prescriptions and at the pharmacy when they attended to collect their prescribed medication. The following selection criteria were defined: (a) inclusion: hypertensive patient aged 25 years or older, on antihypertensive treatment for at least
1 Miguel Martı´nez Community Pharmacy, Benimantell, Spain; 2Department of Clinical Medicine, Miguel Herna´ndez University, San Juan de Alicante, Spain and 3Zeneida Perseguer Community Pharmacy, Petrel, Spain. Correspondence: Professor A Palazo´n-Bru, Department of Clinical Medicine, Miguel Herna´ndez University, Carretera de Valencia-Alicante S/N San Juan de Alicante, Alicante 03550, Spain. E-mail: [email protected] Received 24 August 2013; revised 14 February 2014; accepted 18 February 2014; published online 3 April 2014
Antiplatelet therapy inertia in hypertension MJ Martı´nez-Orozco et al
41 3 months and who agreed to participate in the study. (b) Exclusion: patient refusal to participate in the study, severe concomitant disorders or conditions that the physician or the pharmacist considered could mask the results, any factor related to mental, pathological or social disorders considered by the researcher to hinder or prevent the follow-up, pregnant or lactating women, hypertensive patients involved in another study, hypertensive patients who lived in the same house as somebody else taking the same antihypertensive treatment, hypertensive patients who had no contact phone number to call in the event that they failed to attend, hypertensive patients obtaining their treatment at different pharmacies (this only for the patients at the pharmacy), hypertensive patients for whom it was not possible to determine whether they had taken the AT during the follow-up (the patients were asked to bring their aspirin or clopidogrel packet with them in order to have two quality criteria to determine the taking or not taking of the AT: the office record and the checking of the packets (this only for the patients at the pharmacy)). Of the 767 patients invited to participate, 712 finally finished the study, representing a loss rate of 7.2%, of which 1.7% (n ¼ 13) had one or more exclusion criteria and 5.5% (n ¼ 42) withdrew from the study.
Variables and measurements The principal parameters measured were: Therapeutic inertia if the patient on secondary prevention or primary
prevention with a CEIPC SCORE X10%3 was not prescribed AT by the physician. At the pharmacy, this was assessed after checking the packets brought to the pharmacy by the patient, telephone consultation with the physician and seeing the computerized record of the office. This parameter was measured separately for primary and secondary prevention. Excess antiplatelet prescription in patients who received a prescription despite it not being recommended according to the CEIPC.3 Obviously, this parameter was performed only for primary prevention, because all patients in secondary prevention have the recommendation for AT. Furthermore, the following variables associated with hypertension, according to the European consensus hypertension guidelines,12 were measured: gender, smoking, dyslipidemia, diabetes, personal history of cardiovascular disease (defined by European Society of Hypertension/ European Society of Cardiology guidelines12 or coronary heart disease or stroke, number of drugs for high blood pressure, systolic and diastolic blood pressure, and age; the body mass index was also calculated. In addition, we performed measurements of total cholesterol and highdensity lipoprotein cholesterol to calculate the cardiovascular risk (CEIPC SCORE3 in primary prevention patients. Data on gender, smoking habits, personal history of disease, number of drugs for high blood pressure and age were obtained during the patient interview and corroborated from the clinical records. The blood pressure was measured at each visit taking two measurements, according to the 2007 European guidelines12 with a validated and calibrated automated forearm oscillometric sphygmomanometer (Omron CPII 705, Omron, Kyoto, Japan). The body mass index was calculated using the standard methods to measure weight and height. To obtain the lipid parameters, blood was drawn at the start of the morning after an 8-h fast using calibrated devices. The cardiovascular risk was calculated from the CEIPC SCORE,3 which uses calculations of both total cholesterol and the ratio of total cholesterol to high-density lipoprotein cholesterol; the highest value was used in both cases. At the first visit, the patients were informed about the study and we assessed their exclusion criteria. In addition, the following variables were measured: anthropometric data, smoking habit, the presence of diabetes mellitus and dyslipidemia, a history of cardiovascular disease and the blood pressure. At the second visit, we asked the patients about their drugs and the blood pressure was measured. Finally, at the last visit the drugs and the blood pressure were assessed and we performed the blood tests.
Sample size Of the 712 hypertensive patients analyzed, 108 patients in secondary prevention should have had a recommendation for AT, but 53 of these had inertia. Nine patients in primary prevention should have had the recommendation and all had inertia; because of the small sample size, no further analysis was done in this group. The other 595 patients in & 2015 Macmillan Publishers Limited
primary prevention should have had no recommendation for AT, although 69 of them had a NGRP. Thus, using a 95% confidence level and a maximum expected ratio (P ¼ q ¼ 0.5), the expected error rate in the estimations of inertia in secondary prevention and NGRP in primary prevention were 9.4% and 4.0%, respectively.
Statistical methods The qualitative variables are expressed as exact amounts and percentages and the quantitative variables as mean and standard deviation. A multivariable logistic regression model was performed to estimate adjusted odds ratios (ORs) for relationships between the principal parameters and the study variables. In secondary prevention patients, because of the fact that we had few patients and few events (therapeutic inertia), we selected fewer variables to have a n:k ratio (number of events/number of predictors in the model) greater than 10 (a total of 5 variables in our case, 53/5 ¼ 10.6). The selection strategy performed was: (a) to compare percentages or means of the explanatory variables between having and not having inertia using the w2-tests (Pearson and Fisher) and Student’s t-test, (b) sort the variables according to the P-values obtained (low to high) and (c) select the top 5. Accordingly, in this group of patients, we adjusted the ORs for the chosen variables using the previous strategy. For the patients in primary prevention, there were not enough patients or events (NGRP) to use all the study variables in the model. We therefore adjusted the ORs for gender, smoking, dyslipidemia, diabetes, number of drugs for high blood pressure, systolic blood pressure, diastolic blood pressure, age and body mass index. The lipid parameters were not included in the adjustment because of their collinearity with dyslipidemia. The likelihood ratio test was carried out for the goodness-of-fit of the model. Furthermore, we compared the patients who completed the study with those who withdrew from it, using tests based on the w2 (Pearson and Fisher tests) and Student’s t-test. All analyses were performed at a 5% significance level and associated confidence intervals (CIs) were estimated for each relevant parameter. The statistical analysis was done using IBM SPSS Statistics 19.0 (IBM, Armonk, NY, USA).
Ethical consideration The study afforded no extra risk to the patient and an indirect benefit was expected as the results would improve the use of AT in the primary healthcare setting. The study was conducted according to the principles of the World Medical Association Declaration of Helsinki13 and complied with the norms in the European Union guidelines of good clinical practice. Each patient was informed about the study and the data required, and promised to attend the three visits and do the tests involved. This was done at the first visit where the patient provided signed consent. The study was approved by the Ethics Committee of the Health Department of Elda (Valencian Community).
RESULTS Figure 1 shows the number of patients in each study phase. Of 767 patients invited to participate, 754 were finally included in the study. Of these, 712 completed all three visits and 42 did not. The reasons for withdrawal at the first visit (n ¼ 30) were death (2), wish to cease taking the medication (1), personal reasons (10), not answering the telephone (1), hospital admission (3), pain while taking the blood pressure (2), not bringing the medication in an organized way (1) and unknown (10). The reasons for withdrawal at the second visit (n ¼ 12) were hospital admission (1), change in medication (3), not bringing the prescribed medicine (4), personal reasons (3) and unknown (1). Of the 712 study patients, 117 had a guideline recommendation for AT (7.7%, primary prevention; 92.3%, secondary prevention) and 595 did not. The descriptive characteristics of the study sample (n ¼ 712) are summarized in Table 1. Those patients who completed the study had a high prevalence of cardiovascular risk factors (smoking 16%, dyslipidemia 44.7% and diabetes 23.3%); additionally, about 15% of them were in secondary prevention, they had an advanced age (mean of 63.6 years), and their mean body mass index was greater than 30 kg m 2 (30.3). Regarding comparison of the patients who completed the study with those who withdrew from it, the Journal of Human Hypertension (2015) 40 – 45
Antiplatelet therapy inertia in hypertension MJ Martı´nez-Orozco et al
42
Figure 1.
Hypertensive patients who participated in the study at primary health care in the Valencian Community (Spain), 2007–2009 data.
Table 1.
Descriptive analysis for hypertensive patients who completed or withdrew from the study at primary health care in the Valencian Community (Spain), 2007–2009 data Variable
Antiplatelet therapya Aspirin Clopidogrel Both None Male gender Smoking Dyslipidemia Diabetes Secondary prevention CHD Stroke CEIPC SCORE X10%b Number of drugs for high blood pressurea SBP (mmHg)c DBP (mmHg)c Age (years) BMI (kg m 2) Total cholesterol (mmol l 1)b HDL cholesterol (mmol l 1)b
Completed the study n ¼ 712, n (%)/x (s.d.)
Withdrew from the study n ¼ 42, n (%)/x (s.d.)
Pvalue
103 16 5 588 315 114 318 166 108 44 19 9 2.5
(14.5) (2.2) (0.7) (82.6) (44.2) (16.0) (44.7) (23.3) (15.2) (6.2) (2.7) (1.5) (2.5)
2 (16.7) 0 (0) 0 (0) 10 (83.3) 20 (47.6) 10 (23.8) 14 (33.3) 16 (38.1) 12 (28.6) 1 (2.4) 1 (2.4) NA 1.8 (1.2)
0.674 0.185 0.151 0.030 0.021 0.505 1 NA 0.050
139.6 80.7 63.6 30.3 4.9 1.5
(18.4) (9.8) (11.7) (5.0) ( 0.9) (0.4)
143.5 (19.2) 78.3 (12.6) 67.0 (9.4) 32.2 (6.2) NA NA
0.181 0.235 0.067 0.028 NA NA
0.788
Abbreviations: BMI, body mass index; CEIPC, Interdisciplinary Spanish Committee for Cardiovascular Prevention; CHD, coronary heart disease; DBP, diastolic blood pressure; HDL, high-density lipoprotein; n (%), absolute frequency (relative frequency); NA, not applicable; SBP, systolic blood pressure; x (s.d.), mean (s.d.). aOnly in patients with two or three visits bOnly in patients with primary prevention and three visits. cThe blood pressure mean was calculated using all the patient visits in the study (three visits if they completed the study, one or two visits if they withdrew from the study). The lipids and the CEIPC SCORE do not appear for patients who withdrew from the study because these parameters were measured at the last visit.
Journal of Human Hypertension (2015) 40 – 45
patients who withdrew from the study were significantly (Po0.05) more likely to have diabetes, be in secondary prevention, and have a higher body mass index than those who completed the study. Finally, concerning the antiplatelet medication, we did not find any differences between the two groups. Therapeutic inertia could only be evaluated in secondary prevention (n ¼ 108) and its magnitude was 49.1% (95% CI: 39.6–58.5%). Concerning the type of AT prescribed in those patients who did not experience therapeutic inertia, we found that the most prescribed drug was aspirin (Table 2). In the analysis of factors associated with therapeutic inertia (Table 2), the chosen variables with their P-values in the strategy were: coronary heart disease (o0.001), diastolic blood pressure (0.004), dyslipidemia (0.006), systolic blood pressure (0.076) and gender (0.178). The other P-values (not included in the regression model) were: stroke, 0.240; diabetes, 0.447; smoking, 0.618; body mass index, 0.628; number of drugs for high blood pressure, 0.760; age, 0.815. The logistic regression model showed that the factors associated with higher inertia were being a woman (OR ¼ 0.460, 95% CI: 0.187– 1.133, P ¼ 0.091), no dyslipidemia (OR ¼ 0.393, 95% CI: 0.156– 0.992, P ¼ 0.048), no coronary heart disease (OR ¼ 0.215, 95% CI: 0.086–0.539, P ¼ 0.001), low systolic blood pressure (OR ¼ 0.993, 95% CI: 0.959–1.027, P ¼ 0.667) and high diastolic blood pressure (OR ¼ 1.076, 95% CI: 1.014–1.142, P ¼ 0.016). NGRP was present in 69 of 595 patients (11.6%, 95% CI: 9.0–14.2%). By definition, this was only evaluated in primary prevention, as all patients in secondary prevention are recommended to receive AT. The AT used for the patients with a NGRP was aspirin (62), clopidogrel (4) and both (3; Table 3). Furthermore, Table 3 summarizes the factors that were associated with NGRP. Themost relevant were: gender male (OR ¼ 1.610, 95% CI: 0.930–2.786, P ¼ 0.089), smoking (OR ¼ 2.055, 95% CI: 1.017– 4.152, P ¼ 0.045), dyslipidemia (OR ¼ 3.227, 95% CI: 1.860–5.599, Po0.001) and diabetes (OR ¼ 2.795, 95% CI: 1.604–4.871, & 2015 Macmillan Publishers Limited
Antiplatelet therapy inertia in hypertension MJ Martı´nez-Orozco et al
43 Table 2. Analysis of the inertia for antiplatelet therapy for hypertensive patients in secondary prevention at primary health care in the Valencian Community (Spain), 2007–2009 data Variable
Antiplatelet therapy recommended by guidelines n ¼ 108 n (%)/x (s.d.)
Inertia n ¼ 53 (49.1%) n (%)/x (s.d.)
Adj. OR
95% CI (Adj. OR)
P-value
Antiplatelet therapy Aspirin Clopidogrel Both None
41 12 2 53
Gender Male Femalea
54 (50.0) 54 (50.0)
23 (42.6) 30 (55.6)
0.460
(0.187, 1.133)
0.091
Smokingb Yes No
14 (13.0) 94 (87.0)
6 (42.9) 47 (50.0)
Dyslipidemia Yes Noa
69 (63.9) 39 (36.1)
27 (39.1) 26 (66.7)
0.393
(0.156, 0.992)
0.048
Diabetesb Yes Noa
31 (28.7) 77 (71.3)
17 (54.8) 36 (46.8)
CHD Yes Noa
44 (40.7) 64 (59.3)
12 (27.3) 41 (64.1)
0.215
(0.086, 0.539)
0.001
0.993 1.076
(0.959, 1.027) (1.014, 1.142)
0.667 0.016
Strokeb Yes No Number of drugs for high blood pressureb SBP (mm Hg) DBP (mm Hg) Age (years)b BMI (kg m 2)b
19 89 3.1 135.4 76.4 68.2 29.3
(38.0) (11.1) (1.9) (49.1)
(17.6) (82.4) (2.5) (15.1) (8.9) (8.8) (4.2)
7 (36.8) 46 (51.7) 3.0 (2.5) 138.1(14.5) 78.9 (9.1) 68.0 (8.6) 29.5 (4.3)
Abbreviations: Adj. OR, adjusted odds ratio; BMI, body mass index; CHD, coronary heart disease; CI, confidence interval; DBP, diastolic blood pressure; n(%), absolute frequency (relative frequency); SBP, systolic blood pressure; x(s.d.), mean (s.d.). Likelihood ratio test: w2 ¼ 28.8, Po0.001. OR adjusted for gender, dyslipidemia, CHD, SBP and DBP. aReference. bNot included in the model (see strategy in statistical methods).
Po0.001). None of the other factors was in the least significant (P40.10): higher number of drugs for high blood pressure (OR ¼ 1.031, 95% CI: 0.934–1.138, P ¼ 0.546), higher systolic blood pressure (OR ¼ 1.010, 95% CI: 0.997–1.022, P ¼ 0.130), lower diastolic blood pressure (OR ¼ 0.979, 95% CI: 0.950–1.009, P ¼ 0.169), older age (OR ¼ 1.010, 95% CI: 0.985–1.035, P ¼ 0.429) and higher body mass index (OR ¼ 1.013, 95% CI: 0.959–1.071, P ¼ 0.637). DISCUSSION The patients who withdrew from the study had an increased cardiovascular risk (diabetes, secondary prevention and higher body mass index) as compared with those who remained in the study. As this study was not a clinical trial, this did not represent a selection bias as our objective was to quantify a problem, but not to compare different groups. This study highlights the important degree of therapeutic inertia and NGRP in AT in hypertensive patients. However, because of the very few studies along the same lines, we can only compare our results in such conditions as hypertension and diabetes. Critical review of these studies shows great variability, with 70–85% of poorly controlled patients whose physicians adopt a conservative attitude and prefer not to change the treatment.14–17 Nevertheless, when the study is undertaken among motivated physicians who are aware of the concept of therapeutic inertia, the magnitude of the problem is greatly reduced, with prevalence rates of therapeutic inertia around 33%.16 The lack of similar & 2015 Macmillan Publishers Limited
studies to ours, although, prevents comparison of the magnitude found here, but committing therapeutic inertia in one out of every two hypertensive patients who need AT and the NGRP of AT in one out of every nine patients warrants reflection about changing clinical practice. Consideration should be given to possible episodes of hemorrhage, particularly in patients treated with AT and high blood pressure. The analysis of the factors predicting therapeutic inertia and NGRP reflects the current controversies concerning the indications for AT in hypertensive patients, particularly in primary prevention.8,9,18–20 The results were encouraging in that the patients who were better controlled with AT were precisely those who most needed it, that is, hypertensive patients who had had a coronary heart disease. It should not be forgotten, although, that an important percentage of hypertensive patients with these conditions were not receiving AT. Concerning risk factors, the dyslipidemic patients presented better indices of AT. Nevertheless, these factors should be corroborated with other studies involving a larger sample. The finding of greater NGRP of AT in dyslipidemic and diabetic hypertensive patients could reflect the current controversies about whether these patients should or should not receive AT and the low measurement of cardiovascular risk in these hypertensive patients. The multivariate models only used patient variables, so other factors may influence our indicators; for example, variables associated with the physician–patient relationship, physician training or work setting. Journal of Human Hypertension (2015) 40 – 45
Antiplatelet therapy inertia in hypertension MJ Martı´nez-Orozco et al
44 Table 3. Analysis of the NGRP of antiplatelet therapy for hypertensive patients in primary prevention at primary health care in the Valencian Community (Spain), 2007–2009 data Variable
Antiplatelet therapy not recommended by guidelines n ¼ 595 n (%)/x (s.d.)
NGRP, n ¼ 69 (11.6%) n (%)/x (s.d.)
Adj. OR
95% CI (Adj. OR)
P-value
Antiplatelet therapy Aspirin Clopidogrel Both None
62 4 3 526
Gender Male Femalea
252 (42.4) 342 (57.5)
38 (15.1) 31 (9.1)
1.610
(0.930, 2.786)
0.089
Smoking Yes Noa
91 (15.3) 504 (84.7)
15 (16.5) 54 (10.7)
2.055
(1.017, 4.152)
0.045
Dyslipidemia Yes Noa
246 (41.3) 349 (48.7)
46 (18.7) 23 (6.6)
3.227
(1.860, 5.599)
o0.001
2.795
(1.604, 4.871)
o0.001
1.031 1.010 0.979 1.010 1.013
(0.934, 1.138) (0.997, 1.022) (0.950, 1.009) (0.985, 1.035) (0.959, 1.071)
0.546 0.130 0.169 0.429 0.637
Diabetes Yes Noa Number of drugs for high blood pressure SBP (mmHg) DBP (mmHg) Age (years) BMI (kg m 2) Total cholesterol (mmol l 1) HDL cholesterol (mmol l 1)
133 462 2.5 140.0 81.4 62.8 30.6 4.9 1.5
(10.4) (0.7) (0.5) (88.4)
(22.4) (77.6) (2.5) (18.8) (9.8) (12.0) (5.2) (0.9) (0.4)
62 4 3 0
30 39 2.9 142.1 80.2 64.0 30.8 4.7 1.5
(89.9) (5.8) (4.3) (0.0)
(22.6) (8.4) (3.1) (16.2) (10.9) (14.3) (4.5) (1.1) (0.4)
Abbreviations: Adj. OR, adjusted odds ratio; BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; HDL, high-density lipoprotein; n(%), absolute frequency (relative frequency); NGRP, non-guideline-recommended prescription; SBP, systolic blood pressure; x (s.d.), mean (s.d.). Likelihood ratio test: w2 ¼ 46.9, Po0.001. OR adjusted by gender, smoking, dyslipidemia, diabetes, number of drugs for high blood pressure, SBP, DBP, age and BMI. Lipid parameters not included in the multivariate model due to collinearity with dyslipidemia. aReference.
The importance of our study relates to the lack of other studies that have evaluated jointly the suitability of guidelinerecommended AT, that is, no treatment when indicated or giving treatment when not indicated. This is important because of the strong association and degree of evidence in certain hypertensive patients of the benefits of adequate AT20–23 and the excess risk of hemorrhage in patients receiving AT when it is not indicated.24,25 In clinical practice, being aware of the magnitude of therapeutic inertia and its associated factors is of particular relevance in order to establish strategies to change the situation. We attempted to minimize any possible weakness of the study by using very strict inclusion, exclusion and withdrawal criteria for patient selection in order to provide the best information possible. In addition, we were also very strict when measuring the main variables, as can be seen in the Materials and methods section. Notwithstanding all these precautions, the main limitation was the lack of statistical power in the subgroup analysis. For example, there were only nine patients receiving primary prevention with a SCORE X10% and we could not perform a multivariate analysis with more explanatory variables in the secondary prevention patients. We could not therefore analyze exhaustively the inertia in these subgroups of patients. A larger sample size could possibly have allowed the analysis of these relevant subgroups, considering the poor evaluation of cardiovascular risk and its frequent underestimation, especially in primary prevention.26,27 The indication for AT in secondary prevention is clearer.28 Emphasis should be given to the fact that, even assuming a minimum risk threshold, evidence now exists for the favorable effect of AT in primary prevention. The meta-analysis in the study by Raju et al.21 in the general population and the Fremantle study29 in diabetic patients highlights the benefit of aspirin in Journal of Human Hypertension (2015) 40 – 45
primary prevention. On the other hand, consideration should also be given to the risk of bleeding in the event of inadequate prescription and a balance made when deciding the risk/benefit ratio, as recommended by the various scientific societies.22,30 CONCLUSION In conclusion, in the use of AT to prevent events, both inertia and unsuitable prescription were relatively high. Although certain factors were clearly associated with these phenomena, much still remains to be learnt. As Cocheri recently said in a paper about AT in primary prevention ‘the game is not over’.31
What is known about topic Improving adequate prescription practices for treatment requires that clinicians accept and adopt clinical practice guidelines. The two main factors preventing achievement of the objectives are lack of compliance and therapeutic inertia. Antiplatelet therapy is indicated in hypertensive patients when they have high cardiovascular risk. Just as important as the concept of inertia is excess treatment in the form of prescription of non-guideline-recommended drugs. What this study adds We are unaware of any study evaluating simultaneously both the adequate and the inadequate prescription of antiplatelet therapy in hypertensive patients. As a new feature, we quantify whether hypertensive patients are or are not prescribed suitable antiplatelet therapy, analyzing the excess or deficiency of therapy according to the guidelines.
& 2015 Macmillan Publishers Limited
Antiplatelet therapy inertia in hypertension MJ Martı´nez-Orozco et al
45 CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank everyone who has contributed to the scientific content of the manuscript or provided technical support is in this section. We also thank the Conselleria de Sanitat (Valencian Community) for allowing us to use the equipment of the health centers and the computerized health system. We also thank Armina Sepehri for collaboration in the data computerization process, and Ian Johnstone for help with the English language version of the text. A research grant from the Department of Clinical Medicine at Miguel Herna´ndez University was used to buy reagents for biochemical testing. This was the only role of the funding sources in the study.
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