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14# Research Results in Pharmacology
Research Results in Pharmacology 4(2): 47-58
UDC: 615.036.2 DOI 10.3897/rrpharmacology. 4.27709
3 Research Article
Analysis of changes in pharmacotherapy of stable angina over the five-year period at specialized out-patient level of medical care (pharmacoepidemiological study)
Kristina O. Tsukanova1, Sergey B. Fitilev1, Alexandr V. Vozzhaev1, Irina I. Shkrebneva1, Dmitry A. Klyuev1
1 RUDN University, 6Miklukho-Maklaya St., Moscow 117198, Russian Federation Corresponding author: Kristina O. Tsukanova ([email protected])
Academic editor: Tatyana Pokrovskaya ♦ Received 25 June 2018 ♦ Accepted 27 June 2018 ♦ Published 10 August 2018
Citation: Tsukanova KO, Fitilev SB, Vozzhaev AV, Shkrebneva II, Klyuev DA (2018) Analysis of changes in pharmacotherapy of stable angina over the five-year period at specialized out-patient level of medical care (pharmacoepidemiological study). Research Results in Pharmacology 4(2): 47-58. https://doi.org/10.3897/rrpharmacology.4.27709
Abstract
Introduction: Ischemic heart disease (IHD) remains the leading cause of death both in Europe and in Russia. The most common form of IHD is stable angina. There is compelling evidence that strict adherence to clinical guidelines greatly contributes to mortality reduction. However, the gap between modern knowledge and use of guideline-recommended medications remains significant. As shown by Western practice, one of the possible solutions of this problem is regular conduction of pharmacoepidemiological studies.
Objective: Investigate the dynamics of drug prescription rates in patients with stable angina over the five-year period on the example of routine clinical practice of outpatient cardiology institution of Moscow for the purpose of further eliminating the prescribing gap for guideline recommended pharmacological strategies.
Materials and methods: Our research work was performed as a retrospective pharmacoepidemiological study including two stages with five-year interval using cross-section method.
Results and discussion: We found a significant increase in use of antiplatelets (82.7 vs. 56.2%, p<0.05) and statins (45.6 vs. 16.1%, p<0.05). Despite the unchanged use of ACE inhibitors, the prescription rate of angiotensin receptor blockers II increased (14.7 vs. 9.7%, p<0.05). Analysis of anti-ischemic pharmacotherapy revealed an increase in be-ta-adrenoblockers use (74.3 vs. 63.6%, р<0.05) and a decrease in use of long-acting nitrates (26.3 vs. 31.1%, р<0.05) and calcium channel blockers (35.7 vs. 39.6%, р<0.05). Significant changes were found in prescription rates and dosage regimens of single medications in each pharmacological group. The study results demonstrated an increase in frequency of capturing data on lipid profile and diet recommendations in patient records.
Conclusion: Such type of pharmacoepidemiological study carried out for the first time made it possible to investigate the dynamics of specialists' adherence to guidelines of stable angina pharmacotherapy in routine outpatient clinical practice.
Keywords
antianginal therapy, antiplatelets, ACE inhibitors, beta-adrenoblockers, guideline adherence, guideline implementation, modifiable risk factors , pharmacoepidemiology, prescription rates, routine outpatient practice, secondary prevention, stable angina, statins.
Copyright Kristina O. Tsukanova etal. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Introduction
Cardiovascular disease (CVD) remains the most common cause of death in Europe, accounting for 45% of all deaths (49% of all deaths in women and 40% of all deaths in men). In Europe more than 4 million people die from CVD across the continent every year (Townsend et al. 2016). The contribution of CVD to total mortality in Russia is 57% (Volkova et al. 2015).
Taking into account the fact that ischemic heart disease (IHD) still represents the most common cause of death worldwide producing inestimable invaluable social and economic costs, improving prevention measures is crucial (Chapman et al. 2016). At present there is compelling evidence of the effectiveness of secondary prevention in reducing CVD morbidity and mortality (Pogosova 2014).
The most common form of IHD is stable angina. Onset of this form occurs much earlier in younger Russian patients than in patients from other countries (Shalnova and Deev 2011). This feature emphasizes the importance of preventive pharmacotherapy aimed at prophylaxis of serious complications. It is also important to study pharmacological correction of angina pectoris because it reflects the quality of therapy of the main symptom of stable angina and makes it possible to indirectly form an opinion about the general trend of the "real" clinical practice in the treatment of IHD (Solyanik et al. 2011).
Despite the wide implementation and regular updatеs of treatment guidelines, the gap in the use of guideline recommended medications remains significant as shown in many previous studies and registries of different patient populations with CVD. This problem exists not only in Russia, but also in other countries (Oganov et al. 2007, Tolpygina and Martsevich 2016, Abtan et al. 2016, Eastaugh et al. 2005 , Kotseva et al. 2017 , Ferrari et al. 2015, Olomu et al. 2014, Wilkins et al. 2017).
One of the possible solutions as shown by Western practice is the regular conduct of pharmacoepidemiological studies and registries. Such studies serve as the main source of feedback on prescription rate of guideline recommended medication. The results of such studies allow not only assess the status of the problem in dynamics, but can also be used to develop various administrative measures and educational programs for healthcare professionals and patients.
Only a limited number of pharmacoepidemiological studies focused on the population of stable angina patients have been done by now. Most of the studies were aimed at patients with history of myocardial infarction (MI) and revascularization procedures. A possible reason could be that prognosis of a patient with stable IHD is considered to be relatively favorable.
Among the major international studies and registries with Russian participation, it is necessary to mention ATP (Oganov et al. 2003) and CLARIFY (Shalnova et al. 2013). The results showed that in the Russian population dominating were the patients with more severe functional classes of stable angina. These studies also revealed problems with controlling the target level of blood pressure
(BP), blood lipids and adequate lipid lowering therapy, frequent use of clinically insignificant dosages and the high prevalence of risk factors (RF), such as smoking, overweight and diabetes mellitus (DM). At the same time, Russian clinics involved were mainly institutions with a high level of medical care so the obtained data could be a bit "distorted" in a better way. Thus, the results of national registry "PROGNOZ IHD" demonstrated low prescription rate of drugs recommended by secondary prevention guidelines before admission of patients to cardiology settings and a significant increase in their prescription rate during in-house period (Tolpygina and Martsevich 2016).
Despite the persisting need in the results of this type of pharmacoepidemiological analysis and its relevance to Russian healthcare, recently there has been a tendency to reduce the number of major studies in this field (Petrov 2006). Taking into account regular updates of foreign and national guidelines of secondary prevention and pharma-cotherapy of CVD, it seems essential to carry out such pharmacoepidemiological studies at intervals of four to six years on a regular basis, including separate studies at regional level and in individual medical institutions.
Objective
To investigate the dynamics of drug prescription rates in patients with stable angina over the five-year period on the example of routine clinical practice of outpatient cardiology institution of Moscow for the purpose of further eliminating the prescribing gap for guideline recommended pharmacological strategies in treating patients with IHD (pharmacoepidemiological study).
Materials and methods
Our research was designed as a retrospective pharmaco-epidemiological study, including two stages with a five-year interval using cross-section method at every stage. The object of the research was source medical documentation - outpatient records. The study was approved by the Ethical Committee of Cardiology Dispensary #2 of Healthcare Department of Moscow". The scheme of the study is shown in Figure 1.
At the first stage, a retrospective analysis of medical records of patients with stable angina who primarily visited cardiology clinic in Moscow in 2006 was conducted. The main variables of interest were the prescription rates of medications assigned by cardiologists and the degree of specialists' attention to modifiable risk factors of IHD. The obtained results revealed a significant prescribing gap for guideline recommended medications and low adherence of cardiologists to national IHD management guidelines. On basis of the results of the first stage, some practical activities (use of reminder templates, series of lectures, administrative incentives) were introduced within the institution to increase compliance of specialists
Figure 1. Scheme of retrospective two-stage pharmacoepidemiological study conducted in a specialized outpatient institution.
with clinical guidelines. The second stage was conducted basically in the same methodological way and aimed to assess the degree of success of complex practical activities carried out over the five-year period.
The inclusion of patient medical records into each of the samples was carried out by randomization from records of patients who primarily visited the institution during the analyzed period. The comparative analysis included the data of 2915 outpatient medical records at the first stage and 1633 at the second stage.
Information from patient records was transferred to a specially designed case report form (CRF). CRF included the following sections: patient's social status and demographic data, medical history, instrumental and laboratory tests results, non-pharmacological correction of RF and drug therapy.
Pharmacotherapy (both preventive and anti-ischemic) was analyzed for prescription rates of main groups of drugs and single medications, as well as for dosage regimens. Prescribed pharmacotherapy was compared to the recommendations of national guidelines for secondary prevention and pharmacotherapy of IHD available at the period of study stages (Chazov et al. 2004, Akchurin et al. 2008). The prevalence and correction of modifiable RF were identified by capture degree of this information in patient medical records.
Data from CRFs was transferred to MS Excel database. All statistical tests were performed using SPSS PASW Statistics 22. Continuous variables were expressed as mean and standard deviation, median and 25th and 75th percentiles, minimum and maximum values. Categorical variables were expressed as frequencies and percentages. Student's t-test was used to compare normally distributed continuous data from two independent samples. Mann-Whitney U test was used in case of different distribution and for ordinal scale parameters. Chi square tests were used for nominal variables. In case of restrictions for Chi square test, Fisher's exact test was used. Multi-
ple comparisons of ordinal data were performed using Mann-Whitney U test. In case of significant differences, pairwise comparisons were performed using the Fisher's exact test. Statistical significance was assessed between the data from the first and the second stage of the study. A p-value <0.05 was considered significant.
Results and discussion
Comparative analysis of patients' population
The main demographic and medical history data is presented in Table 1. Women continue to dominate in the gender structure of the analyzed population. However, the analysis of the data revealed a decrease in the number of female patients and an increase in the number of male subjects at the second stage of the study.
Over the period of five years, the mean age of a patient with stable angina remained almost the same: 65.73±9.10 years and 66.78±9.46 years, respectively. The analysis of the dynamics of patient age distribution revealed that the majority of subjects belonged to the age group over 60 years. At both stages of the study, there were less than 30% of patients under 60 years of age. Patients with stable angina class II and class III according to the Canadian Cardiovascular Society (CCS) classification continued to dominate within the study population at each stage.
High frequency of cardiovascular concomitant diseases was revealed in addition to the history of stable angina, according to the patients' medical records. At the second stage of the study, the following conditions were detected significantly more often: hypertension, chronic heart failure (CHF), diabetes mellitus, and various heart rhythm disturbances. The number of patients with prior MI increased more than 1.5 times, which can be explained by lack of secondary prevention measures.
Table 1. Demographics and clinical characteristics of the patient populations under study
Variables
2006 (n=2915)
2011 (n=1633)
Gender: Male, n (%) Female, n (%) Age (y), mean±SD Angina CCS Class:
I, n (%)
II, n (%)
III, n (%)
IV, n (%)
Prior myocardial infarction, n (%) Arterial hypertension, n (%): Grade 1 Grade 2 Grade 3
Chronic heart failure, n (%) Prior stroke, n (%) Diabetes mellitus, n (%) Different types of arrhythmias, n (%)
977 (33.5) 1936 (66.4) 65,73±9,10
91(3.1) 2458 (84.3) 305 (10.5)
3 (0.1) 640 (22,0) 2674 (91.7) 108 (4.0) 689 (25.8) 1826 (68.3) 1562 (53.6) 152 (5.2) 398 (13.7) 650 (22.3)
693 (42.4)* 940 (57.6)* 66,78±9,46*
40 (2.4) 1420 (87.0)* 154 (9.4) 2 (0.1) 624 (38.2)* 1526 (93.4)*
52 (3.4) 345 (22.6) * 1104(72.3)* 1254 (76.8)* 119 (7.3)* 357 (21.9)* 439 (26.9)*
Note: *p<0.05 in comparison with the year of 2006; CCS - Canadian Cardiovascular Society.
Analysis of the prescription rates dynamics of secondary prevention drugs in patients with stable angina
For patients with stable angina, an integral part of preventing CVDs and their complications, according to the Russian and international clinical guidelines, is the prescription of drugs with a proven ability to prevent the risk of cardiovascular events - antiplatelet agents, statins, beta-adrenoblockers (BBs) (history of MI or CHF) and angiotensin-converting enzyme (ACE) inhibitors (if intolerable or contraindicated - angiotensin II receptor blockers (ARBs)). Despite the fact that BBs are important for improving the prognosis in patients with stable angina, the data obtained on prescription rates and dosage regimen of BBs is presented within the analysis of an-ti-ischemic pharmacotherapy. Furthermore, BBs are the first line drugs to relieve angina symptoms, according to guidelines.
Dynamics of prescription rates of secondary prevention drugs recommended to patients with stable angina is presented in Table 2. It should be noted that significant changes were revealed in comparison with the first stage of the study: a higher frequency of recommendations for antiplatelets and an almost threefold increase in the frequency of prescribing statins. The use of ACE inhibitors remained at the same level, whereas the frequency of ARBs increased significantly.
At the same time, antiplatelet agents and statins (must be prescribed to all patients with stable angina) were recommended only to 665 patients at the second stage of the study (40.7%). Significant changes were also detected in prescription rates of single medications and their dosage regimens in each pharmacological group.
Analysis of the prescription rates dynamics of antipla-telet agents
A significant increase in antiplatelets use (up to 83.0%) was found. However, the same value was 90% or more in Russian population of patients, looking at the results of studies PROGNOZ IHD (Tolpygina and Martsevich 2016), EUROASPIRE IV (Pogosova et al. 2016), CLARIFY (Shalnova and Deev 2011).
Prescription rates of acetylsalicylic acid (ASA) as monotherapy decreased significantly. This was partially due to an increase in use of ASA in combination with clopidogrel. Dual antiplatelet therapy (DAPT) was implemented into clinical practice at the time of the second stage of the study (Table 3). At the same time, the proportion of patients with indications for DAPT (one-year history of MI and/or interventional procedure) was 14.8%.
Prescription rates of daily ASA doses also changed over the five-year period. The number of patients receiving ASA at adequate doses of 100 mg and 75 mg increased significantly (Table 4). ASA 50 mg was also prescribed frequently in spite of the fact that the guidelines instruct to use ASA at doses of 75-150 mg. As a positive aspect, it should be noted that physicians almost stopped to use the dose of 125 mg which was prescribed as "aspirin and gave favor to ASA drugs in form of tablets coated with an intestinal membrane or ASA with antacids (magnesium hydroxide).
In general, the changes which had happened over the five-year period in antiplatelet pharmacotherapy can be assessed positively. But still significant reserves remain for further optimization of DAPT as well as for prescriptions rates and adequate dosage regimens.
Table 2. Dynamics of prescription rates of secondary prevention drugs
Pharmacological groups First stage (n=2915) Second stage (n= =1633)
Number of patients % Number of patients %
Antiplatelet agents 1639 56.2 1351 82.7 p<0.05
Statins 469 16.1 745 45.6 p<0.05
ACE inhibitors (including 2028 69.6 1104 67.6 p>0.05
combination medications)
ARBs (including combination medications) 282 9.7 240 14.7 p<0.05
Note: ACE - angiotensin-converting enzyme; ARB - angiotensin II receptor blockers.
Table 3. Dynamics of prescription rates of antiplatelet agents
Antiplatelets First stage Second stage
Number of patients % Number of patients %
ASA (including combination medications) 1627 99.3 1256 93.0 p<0.05
Dual antiplatelet therapy (ASA + Clopidogrel) 3 0.2 73 5.4 p<0.05
Clopidogrel 5 0.3 21 1.6 p<0.05
Ticlopidine 4 0.2 1 0.1 p>0.05
Total: 1639 100 1351 100
Note: ASA - acetylsalicylic acid.
Table 4. Dynamics of prescription rates of daily ASA doses
Daily ASA doses (mg)
First stage
Second stage
Number of patients
%
Number of patients
%
Statistical significance
500 1 0.1 - - -
250 7 0.4 - - -
150 14 0.9 13 1.0 p>0.05
125 614 37.7 6 0.5 p<0.05
100 782 48.0 945 71.1 p<0.05
75 28 1.7 150 11.3 p<0.05
50 117 7.2 194 14.6 p<0.05
No data 67 4.1 21 1.6 p<0.05
Total 1630 100 1329 100
Note: ASA - acetylsalicylic acid.
Analysis of the prescription rates dynamics of statins
The number of important changes were revealed in statin therapy along with a significant increase in statin use frequency on the whole. Cardiologists significantly more often recommended atorvastatin at the second stage of the study, but simvastatin prescription rate comparably reduced. Rosuvastatin prescriptions were very rare at both stages, possibly due to its high cost and availability of only one analogue drug. Such medications as fluvastatin and lovastatin were not used at the second stage (Table 5).
The analysis of dosage regimens of statins demonstrated an increased use of leading statins in higher doses. Thus, simvastatin 20 mg was prescribed significantly more often and simvastatin 10 mg - almost twice as rarely at the second stage of the study. The dose of 40 mg was prescribed only in a few cases at both stages (Table 6).
More than 50% of patients received atorvastatin 10 mg at both stages of the study despite the significant increase in its use of 20 mg dose. Atorvastatin 40 mg was prescribed only in a few cases at the second stage (Table 7).
On one hand, the above results look promising and can contribute to improving the efficacy of lipid-lowering pharmacotherapy and to achieving target levels for total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). But on the other hand, more than 50% of patients have not received statins as part of secondary prevention therapy.
Analysis of the prescription rates dynamics of ACE inhibitors and angiotensin II receptor antagonists
Both monotherapy and combination drugs (fixed combinations with diuretics or calcium antagonists) were taken
Table 5. Dynamics of prescription rates of statins
Statins
First stage
Second stage
Number of patients
%
Number of patients
%
Statistical significance
Atorvastatin
Simvastatin
Rosuvastatin
Lovastatin
Fluvastatin
Total:
216 248 1 3 1
469
46.1 52.9 0.2 0.6 0.2 100
394 339 12
745
52.9 45.5 1.6
100
p<0.05 p<0.05 p<0.05
Table 6. Dynamics of prescription rates of daily Simvastatin doses
Daily Simvastatin doses (mg)
First stage
Second stage
Number of patients
%
Number of patients
%
Statistical significance
5 10 20 40
No data Total
1
149 85 8 5 248
0.4 60.1 34.3 3.2 2.0 100
2 122 205 8 2
339
0.6 36.0 60.5 2.4 0.6 100
p>0.05 p<0.05 p<0.05 p>0.05 p>0.05
Table 7. Dynamics of prescription rates of daily Atorvastatin doses
Daily Atorvastatin doses (mg)
First stage
Second stage
Number of patients
%
Number of patients
%
Statistical significance
5 10 20 40
No data Total
1
150 64
1
216
0.5 69.4 29.6
0.5 100
212 165 14 3 394
53.8
41.9 3.6 0.8 100
p<0.05 p<0.05
p>0.05
into account when analyzing the use of ACE inhibitors and ARBs.
The prescription rate of ACE inhibitors as a whole group remained at the level of 70% throughout the five-year period. The most frequently prescribed drugs remained enalapril, perindopril and fosinopril. At the same time, the enalapril prescription rate increased significantly at the second stage of the study. Perhaps this happened due to its proven efficacy in patients with CHF and MI, whose number was higher at the second stage of the study. The prescription rates of perindopril and lisinopril also increased; however, the rate of fosinopril prescription decreased. The proportion of other ACE inhibitors (cap-topril, ramipril, quinapril) decreased significantly. Especially strange was the reduction in the use of ramipril because, according to the guidelines, ramipril is a preferred ACE inhibitor for patients with stable angina (Table 8).
The dosage regimen analysis revealed significant changes only for enalapril. A significant decrease in use of enalapril at higher daily doses of 20 mg and 40 mg was accompanied by an increased use of minimal and average doses - 2.5 mg, 5 mg and 10 mg (Table 9).
It was necessary to take into account that at the time of the first stage of the study, perindopril was marketed as perindopril tretbutylamine form and at the time of the second stage - as perindopril arginine form. The doses
of tertbutylamine perindopril - 2 mg, 4 mg and 8 mg -correspond to the doses of 2.5 mg, 5 mg and 10 mg of perindopril arginine. Dosage regimen of perindopril was similar at both stages of the study. Perindopril at the dose of 5 mg was recommended to 184 patients (47.8%) at the first stage and to 134 patients (50.4%) at the second stage. Perindopril at the dose of 2.5 mg was recommended to 140 patients (36.2%) at the first stage and to 79 patients (29.7%) at the second stage. Perindopril was prescribed to 50 patients (12.9%) at the first stage and 43 patients (16.2%) at the second stage (p>0.05) at the maximal daily dose of 10 mg.
Due to the fact that according to the guidelines ACE inhibitors should be replaced by ARBs in cases of intolerance or contraindication, it seemed important to analyze prescription rates of ARBs (Table 10). Losartan remained the most commonly used drug among ARBs (p.>0.05). The frequency of valsartan prescriptions was about 10% at each stage of the study. Telmisartan, candesartan, epro-sartan, olmesartan were recommended in a few cases.
Despite a significant increase in prescription rates of losartan at the dose of 100 mg, the dose of 50 mg was still prescribed in more than 50% cases at both stages of the study. The dose of 12.5 mg was not recommended at the second stage, while the prescription frequency of the dose of 25 mg increased significantly (Table 11).
Research Results In Pharmacology 4(2): 47-58 53
Table 8. Dynamics of prescription rates of ACE inhibitors
ACE inhibitors First stage Second stage
Number of patients % Number of patients %
Enalapril 883 43.5 558 50.5 p<0.05
Perindopril 386 19.0 266 24.1 p<0.05
Fosinopril 413 20.4 156 14.1 p<0.05
Lisinopril 91 4.5 95 8.6 p<0.05
Ramipril 48 2.4 11 1.0 p<0.05
Captopril 94 4.6 9 0.8 p<0.05
Quinapril 108 5.3 7 0.6 p<0.05
Trandolapril - - 1 0.1 -
Zofenopril - - 1 0.1 -
Moexipril 1 0.1 - - -
Cilazapril 1 0.1 - - -
Spirapril 3 0.2 - - -
Total: 2028 100 1104 100
Note: ACE - angiotensin-converting enzyme.
Table 9. Dynamics of prescription rates of daily Enalapril doses
Daily Enalapril doses (mg) First stage Second stage
Number of patients % Number of patients %
40 62 7.0 23 4.1 p<0.05
30 13 1.5 1 0.2 p<0.05
20 386 43.7 163 29.2 p<0.05
15 2 0.2 2 0.4 p>0.05
10 288 32.6 212 38.0 p<0.05
5 79 8.9 100 17.9 p<0.05
2,5 27 3.1 49 8.8 p<0.05
1,25 - - 2 0.4 -
No data 26 2.9 6 1.1 p>0.05
Total 883 100 558 100
Table 10. Dynamics of prescription rates of angiotensin II receptor antagonists
Angiotensin II receptor antagonists First stage Number of patients % Second stage Number of patients % Statistical significance
Losartan 249 88.3 209 87.1 p>0.05
Valsartan 24 8.5 26 10.8 p>0.05
Telmisartan 4 1.4 1 0.4 p>0.05
Eprosartan - - 1 0.4 -
Candesartan - - 2 0.8 -
Olmesartan - - 1 0.4 -
Irbesartan 5 1.8 - - -
Total: 282 100 240 100
Table 11. Dynamics of prescription rates of daily Losartan doses
Daily Losartan First stage Second stage
doses (mg) Number of patients % Number of patients %
12.5 16 6.4 - - -
25 6 2.4 17 8.1 p<0.05
50 192 77.1 140 67.0 p<0.05
100 26 10.4 40 19.1 p<0.05
No data 9 3.6 12 5.7 p>0.05
Total 249 100 209 100
Summing up the results describing the dynamics of na receiving these medications increased over five years. prescriptions rates of ACE inhibitors and ARBs, it should The tendency regarding the use of minimal and average be noted that the proportion of patients with stable angi- doses remains.
Analysis of the prescription rates dynamics of an-ti-ischemic drugs in patients with stable angina
The main purpose of stable angina treatment is not only to improve prognosis (prevention of complications and mortality), but also to improve the quality of patients' life (associated with a lower frequency and intensity of angina attacks).
The Russian and international guidelines recommend the following pharmacological groups of anti-ischemic drugs: beta-blockers, calcium channel blockers (CCBs), long-acting nitrates, If-channel blockers (selective inhibition of the sinus node /(f) pacemaking current), K+-chan-nel activators (stimulation of ATP-sensitive potassium channels), myocardial cytoprotectors - trimetazidine and ranolazine. The analysis of the prescription rates dynamics of the main groups of anti-ischemic drugs revealed significant changes (Table 12).
Above all, a higher prescription rate of BBs and a lower prescription rate of long-acting nitrates should be noted. Also, the second stage results revealed significant reduction in prescription rates of CCBs and trimetazidine.
Analysis of the prescription rates dynamics of be-ta-adrenoblockers
The prescription rate of the group of BBs increased by 10.7% over the five-year period. That could be recognized as a positive trend. The analysis of prescription rates of different BBs identified a number of significant changes. Thus, bisoprolol was prescribed almost twice as often and took a leading position, replacing metoprolol at the second stage of the study. Specialists started prescribing nebivolol more frequently and atenolol - less. Other BBs had a very small share of prescriptions within the group (Table 13). A significant increase in the use of bisoprolol and nebi-valol can be explained by a larger proportion of patients with DM and chronic obstructive pulmonary disease at the second stage of the study. It is common knowledge that these drugs are more cardioselective in comparison with other BBs. Absence of prescriptions of non-selective pro-pranolol at the second stage is definitely a positive finding.
The analysis of dosage regimens of BBs revealed significant changes only regarding bisoprolol. Over the five-year period, the prescription rate of the dose of 5 mg decreased, while the rate of the dose 10 mg increased (Table 14). Bisoprolol at the dose of 20 mg was recommended only at the second stage of the study in individual cases. The minimal therapeutic dose of 2.5 mg started being used more often.
Along with bisoprolol, other BBs were still prescribed at minimal doses: metoprolol 50 mg - 56.3% (451 patients) and 51.5% (171 patients), atenolol 50 mg - 63.7% (116 patients) and 62.2% (23 patients) at the first and the second stage of the study, respectively. The results obtained on BB dosage regimens can be explained by high comorbidity rates (CHF, DM, COPD) requiring the use of minimal doses with gradual titration.
The study results demonstrated positive dynamics in terms of prescription rates of BBs and a more frequent choice of cardioselective medications. However, the fact that at the second stage BBs were not prescribed to approximately 25% of patients causes concern.
Analysis of prescription rates dynamics of calcium channel blockers
Calcium channel blockers are second-line agents (in accordance with the guidelines of the Russian Society of Cardiology effective at time of the second stage of the study) in patients with stable angina and recommended in cases of poor tolerance or low efficacy of BBs (Class I, Level A). The study results demonstrated the reduction in prescription rates of CCBs over the five-year period (p<0.05). Within the group, dihydropyridines CCBs were prescribed in major cases (over 80%). Non-dihydropyri-dine CCBs were prescribed in 18.7% of cases at the first stage and in 15.8% of cases at the second stage. High prescription rates of dihydropyridines CCBs were most likely caused by high prevalence of hypertensives (more than 90%) at both study stages. It is important to mention that amlodipine prescription rate increased and the nifedipine rate decreased (Table 15). The fact that specialists preferred amlodipine to nifedipine is undoubtedly recognized as a positive trend.
It is also very important to note the revealed changes in amlodipine dosage regimen. The dose of 5 mg was prescribed at a lower rate, but the maximal recommended therapeutic dose of 10 mg was prescribed more often at the second stage of the study (Table 16). The dose of 2.5 mg was prescribed in 6.4% and 6.5% of cases at the first and the second stage, respectively. The use of this low dose might be justified by taking into account a large proportion of elderly patients and high prevalence of CHF.
Analysis of the prescription rates dynamics of long-acting nitrates
If CCB monotherapy or combination therapy of CCB and BB is ineffective, it is necessary to replace CCB by long-acting nitrate, according to the current clinical guidelines. The results of the present study revealed a significant decrease in nitrates use that can be recognized as a positive trend. There were no significant changes in the group structure. Cardiologists continued to recommend isosorbide dinitrate in more than 50% of cases.
Analysis of the prescription rates dynamics of other anti-ischemic drugs
Following the actual classification, among the anti-ische-mic medications recommended for the treatment of stable angina are also ivabradine, nicorandil, ranolazine, and tri-metazidine. The present paper looked only at the prescription dynamics of ivabradine and trimetazidine. Nicorandil and ranolazine were not included into the guidelines ef-
Table 12. Dynamics of prescription rates of anti-ischemic drugs
Pharmacological groups First stage (n=2915) Second stage (n=1633)
Number of patients % Number of patients % Statistical significance
Beta-blockers (including combination medications) 1853 63.6 1213 74.3 p<0.05
Calcium channel blockers 1154 39.6 583 35.7 p<0.05
(including combination medications)
Long-acting nitrates 906 31.1 429 26.3 p<0.05
Trimetazidine 724 24.8 234 14.3 p<0.05
Ivabradine - - 12 0.7 -
Table 13. Dynamics of prescription rates of beta-blockers
Beta-blockers First stage Second stage
Number of patients % Number of patients % Statistical significance
Bisoprolol 610 32.9 667 55.0 p<0.05
Metoprolol 801 43.2 332 27.4 p<0.05
Nebivolol 38 2.1 101 8.3 p<0.05
Carvedilol 110 5.9 74 6.1 p>0.05
Atenolol (including combination medications) 182 9.8 37 3.1 p<0.05
Betaxolol 103 5.6 2 0.2 p<0.05
Propranolol 9 0.5 - - -
Total: 1853 100 1213 100
Table 14. Dynamics of prescription rates of daily bisoprolol doses
Bisoprolol daily doses (mg) First stage Second stage
Number of patients % Number of patients % Statistical significance
20 - - 3 0.5 -
10 30 4.9 62 9.3 p<0.05
7.5 2 0.3 7 1.0 p>0.05
5 390 63.9 321 48.1 p<0.05
2.5 175 28.7 264 39.6 p<0.05
1.25 2 0.3 7 1.0 p>0.05
No data 11 1.8 3 0.5 p>0.05
Total 610 100 667 100
Table 15. Dynamics of prescriptions rates of calcium channel blockers
Calcium channel blokers First stage Second stage
Number of patients % Number of patients % Statistical significance
Amlodipine 511 44.3 345 59.2 p<0.05
Nifedipine 354 30.7 96 16.5 p<0.05
Felodipine 72 6.2 48 8.2 p>0.05
Lercanidipine 1 0.1 2 0.3 p>0.05
Verapamil 164 14.2 71 12.2 p>0.05
Diltiazem 52 4.5 21 3.6 p>0.05
Total: 1154 100 583 100
Table 16. Dynamics of prescription rates of daily Amlodipine doses
First stage Second stage
Daily Amlodipin doses (mg) -Statistical significance
Number of patients % Number of patients %
2.5 32 6.3 22 6.4 p>0.05
5 325 63.6 185 53.6 p<0.05
10 131 25.6 123 35.7 p<0.05
20 6 1.2 7 2.0 p>0.05
No data 17 3.3 8 2.3 p>0.05
In total 511 100 345 100
fective at time of the study. Ivabradine was included into the guidelines only in 2008. The proportion of ivabradine prescriptions at the second stage of the study was extremely low. The prescription rate of trimetazidine decreased significantly over the five-year period (Table 12).
Analysis of dynamics of specialists' attention to modifiable risk factors
An analysis of changes in the degree of cardiologists' attention to modifiable RFs was conducted because all the IHD management guidelines recommend to pay special attention to the identification and correction of RFs. Non-pharmacological measures are considered to be very important and include smoking cessation, diet, physical activity, weight loss, etc.
A full-scale analysis of the prevalence of modifiable cardiovascular RFs in patients with stable angina failed due to insufficient capture of relevant information in their medical records. Nevertheless, information concerning modifiable RFs was captured more frequently at the second stage of the study. Thus, the data on smoking status were present in 27.6% (450 patients) of records, on the attitude to alcohol - in 21.5% (351 patients) of records, while at the first stage such information was captured only in 2.4% (70 patients) and 0.3% (9 patients) of records, respectively (p<0.05). Almost no changes were recorded regarding the capture of anthropometric parameters allowing to estimate patient's body mass index (p>0.05). This information was present in 13.6% (396 patients) of records at the first stage and in 15.7% (256 patients) of records at the second stage. None of the medical records contained such a parameter as waist circumference. The data on physical activity and diet was available in more than 95% of records at both stages of the study.
The analysis of data completeness concerning the lip-id profile revealed a significant increase in the degree of cardiologists' attention to all lipid parameters over the five-year period. Almost doubled frequency of capturing data on LDL-C levels is undoubtedly a positive trend. Attention of specialists to other lipids also became higher. Thus, the frequency of capturing data on high density lipoprotein cholesterol (HDL-C), triglycerides (TG) and total cholesterol significantly increased (Table 17).
The study results demonstrated some positive dynamics regarding completeness of data on modifiable RFs in patients' medical records, but still the degree of specialists' attention to such an important aspect of preventive non-pharmacological treatment remains insufficient.
It is also necessary to point out that lack of adequate measures for non-pharmacological correction of cardiovascular RFs was revealed. Thus, recommendations to do physical activity decreased from 23.5% (686 patients) to 14.9% (244 patients). Only five smokers at the first stage and 10 smokers at the second stage received written advice to stop smoking. The positive dynamics was detected in terms of correction of such a risk factor as improper nutrition. Frequency of diet recommendations increased from 50.1% (1461 patients) to 66.6% (1087 patients).
Conclusion
Thus, the present pharmacoepidemiological study allowed to investigate the dynamics of the gap between the guidelines recommended for pharmacological strategies and prescriptions when managing patients with stable angina in routine clinical practice of a specialized outpatient institution. The results obtained demonstrated an increase in prescription rates of key pharmacological groups that improve prognosis in IHD: antiplatelets (82.7 vs. 56.2%, p<0.05), statins (45.6 vs. 16.1%, p<0.05) and ARBs (14.7 vs. 9.7%, p<0.05) as well as increasing the frequency of recommending BBs (74.3 vs. 63.6%, p<0.05) and long acting nitrates (26.3 vs. 31.1%, p<0.05) and CCBs (35.7 vs. 39,6%, p<0.05) as components of anti-ischemic therapy. The study also revealed an increase in prescription rates of individual medications at higher daily doses: ASA at the dose of 100 mg (71.1 vs. 48.0%, p<0.05), simvastatin and atorvastatin at the dose of 20 mg (60.5 vs. 34.3%, p<0.05 and 41.9 vs. 29.6%, p<0.05, respectively). However, the situation can't be regarded as satisfactory. Therefore, a number of practical recommendations were developed to further improve the compliance of specialists' recommendations with the clinical guidelines at the outpatient level of routine medical care. The present study significantly contributes to mortality reduction and life expectancy increase in patients with IHD by improving the adherence of specialists to the clinical guidelines. Yet, the problems of patients following a prescribed pharma-cotherapy and interchangeability of drugs are extremely important in this context and, hence, require further study.
In conclusion, the results obtained in the present study concerning IHD pharmacotherapy and changes which occurred over the five-year period are consistent in many aspects with a number of national and foreign studies on the similar problem. This fact emphasizes their credibility and importance for practical health care.
Table 17. Dynamics of capturing information on lipid profile in patients' medical records
Lipids First stage (n=2915) Second stage (n= =1633)
Number of patients % Number of patients %
Total cholesterol 1291 44.3 1088 66.6 p<0.05
LDL-C 495 17.0 541 33.1 p<0.05
TG 1041 35.7 808 49.5 p<0.05
HDL-C 440 15.1 445 27.3 p<0/05
Note: LDL-C - low-density lipoprotein cholesterol; TG - triglycerides; HDL-C - high density lipoprotein cholesterol.
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Author Contributors
■ Kristina O. Tsukanova, post-graduate student of the Department of Pharmacology and Clinical Pharmacology, Medical institution, RUDN University, email: [email protected]. The author had the primary role in collection, analysis and interpretation of the data for publication.
■ Sergey B. Fitilev, Professor of the Department of Pharmacology and Clinical Pharmacology, Medical institution, RUDN University, Doctor of Medical Sciences, Professor, email: [email protected]. The author was the research supervisor, and contributed to the concept and design of the work, analysis and interpretation of the study results.
■ Alexandr V. Vozzhaev, Associate Professor of the Department of Pharmacology and Clinical Pharmacology, Medical institution, RUDN University, Candidate of Biological Sciences, email: [email protected]. The author was the scientific consultant, took part in the development of the methodology of work, optimization of the tools for collecting and processing clinical data, as well as in interpreting the results of the study.
■ Irina I. Shkrebneva, Associate Professor of the Department of Pharmacology and Clinical Pharmacology, Medical institution, RUDN University, Candidate of Medical Sciences, Associate Professor, email: ishkrebneva@yandex. ru. The author provided critical analysis of the intellectual content.
■ Dmitry A. Klyuev, student, Medical institution, RUDN University, email: [email protected]. Contribution: statistical data processing and translation in English
