ijcsInternational Journal of Cardiovascular SciencesInt. J. Cardiovasc. Sci.2359-48022359-5647Sociedade Brasileira de CardiologiazvcJgKfnYZ8BpqMq3HS6wVhS2359-5647201700010000410.5935/2359-4802.20170015Original ArticlesCardiovascular Lipid Risk Factors and Rate of Cardiovascular Events After Myocardial RevascularizationCatalinaCosor Oana1AdinaBucur1SmaranditaBaibata Emilia Dana1AngelaDragomir2DanGaita1SilviaMancas1University of Medicine and Pharmacy Victor Babes TimisoaraRomaniaUniversity of Medicine and Pharmacy Victor Babes Timisoara - RomaniaThe Institute of Cardiovascular Disease TimisoaraRomaniaThe Institute of Cardiovascular Disease Timisoara - RomaniaMailing Address: Cosor Oana Catalina. Str.Arh.V.Vlad,bl 13 ,sc D,ap 2 - 13. Postal Code 035332, Timisoara - Romania. E-mail: andrei.csr@gmail.com
Author contributions
Conception and design of the research: Catalina CO, Silvia M. Acquisition of data: Catalina CO, Smarandita BED. Analysis and interpretation of the data: Catalina CO, Adina B. Statistical analysis: Angela D. Obtaining financing: Dan G. Writing of the manuscript: Catalina CO, Silvia M. Critical revision of the manuscript for intellectual content: Dan G, Silvia M.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Jan-Feb2017301410031020162110201621112016This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.AbstractBackground:
Coronary heart disease is a public health problem, and the leading cause of premature death in Europe and worldwide. There is epidemiological evidence that the control of cardiovascular risk factors following myocardial revascularization remains suboptimal.
Objectives:
Analyze the incidence of cardiovascular events in patients receiving secondary prevention therapies after myocardial revascularization.
Methods:
Single-center study on consecutive coronary patients retrospectively identified, conducted at the Institute of Cardiovascular Diseases in Timisoara, Romania. Patients with diagnosis of revascularization for coronary artery disease (percutaneous coronary intervention, PCI or coronary artery bypass grafting, CABG) were included, following the inclusion criteria of the EuroAspire IV study. Outcome measures were assessed at three time points- at T0, when myocardial revascularization was performed; at T1 (interview with patients who had undergone revascularization for more than 6 months and less than 5 years), and T2 (interview with patients who had undergone revascularization for more than 5 years). Associations of primary and secondary lipid targets with the rates of adverse cardiovascular events (MACE) were assessed at T2.
Results:
Of 375 coronary patients, 341 were included in the study. At T1, 5% and 34.9% of patients reached the LDL-c and non-HDL-c target respectively. MACE rate at T2 was 7.9% in a median of 4.33 years of follow-up. We found a positive, statically significant association between MACE rate and LDL-c at T1 (p = 0.039). There were significant differences in mean non-HDLc levels between MACE categories at T1 (p = 0.02). There was a significant association between mean non-HDL with the incidence of heart failure (p = 0.007), newly diagnosed diabetes (p = 0.017) and restenosis rate (p = 0.004).
Conclusion:
The study highlights the need to control lipid risk factors after myocardial revascularization procedures, even at long-term, to minimize the risk of cardiovascular events in patients with coronary diseases.
Coronary heart disease remains "the scourge of the modern world" despite advances made in the field. It is a public health problem, and the leading cause of premature death in Europe and worldwide.1
In this study, we focused on understanding the evolution of the atherothrombotic process in coronary symptomatic patients who underwent coronary revascularization: percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).
The relationship between low-density lipoprotein cholesterol (LDL-c) and the incidence of cardiovascular events has been demonstrated by numerous epidemiological studies: CARDS2 ASPEN3 ASCOT.4 The New European Society of Cardiology (ESC) Guidelines for Cardiovascular Disease Prevention recommended LDL-c target levels of lower than 70 mg/dL for coronary patients at high risk and very high risk5. In addition, patients under statin therapy may also be at very high cardiovascular risk.5-6
The EuroAspire III and IV trials represent the epidemiological evidence that the control of modifiable cardiovascular risk factors among coronary patients remains suboptimal.6-7
The hypothesis of our research was that an inefficient control of cardiovascular risk factors would have a long-term effect on the incidence of fatal and non-fatal cardiovascular events. In this context, our study aimed to analyze the incidence of fatal and non-fatal cardiovascular events in coronary patients under statin therapy years after coronary revascularization, following the ESC prevention of cardiovascular disease program criteria.5
Methods
This is a single-center study conducted at the Institute of Cardiovascular Disease, Timisoara, Romania. The inclusion criteria followed the EUROASPIRE IV protocol. A total of 375 consecutive coronary patients aged 18-80 years with definite diagnosis of revascularization for coronary artery disease (PCI, CABG) were retrospectively identified. Of them, 341 were considered eligible and 341 were included in the study (Figure 1). Clinical data of patients were assessed at three time points - at T0, when successful revascularization was identified, at T1 (from 6 months to 3 years post-myocardial revascularization), and at T2 (from 3 to 5 years post-myocardial revascularization).
Study design; PTCA: percutaneous transluminal coronary angioplasty; MACE: major adverse cardiovascular events; CABG: coronary artery bypass grafting
The following data was collected on an electronic database: lipid profile data - total cholesterol (TC); triglycerides, (TG); high-density lipoprotein cholesterol (HDL-c); LDL-c; non-HDL-c calculated as TC minus HDL-c8 - number of fatal / non-fatal cardiovascular events; major adverse cardiovascular events (MACE): cardiovascular death, noncardiovascular death, restenosis, stroke / transient ischemic attack (TIA) - electrostimulation by pacemaker, hospitalization for reintervention - percutaneous transluminal coronary angioplasty (PTCA) or CABG, hospitalization for heart failure, diagnosis of diabetes mellitus. New lipid risk was evaluated at T0 and T1, following the European Cardiovascular Prevention criteria (5). The rate of fatal and nonfatal cardiovascular events was analyzed based on the potential cardiolipidic risk.
Patients' follow-up was conducted by a questionnaire validated for the countries that participated in the EUROASPIRE IV study.6 At inclusion, we used the post-revascularization protocols specified in the ESC guidelines for secondary cardiovascular prevention (2012)9, adopted by the Romanian Society of Cardiology.
Statistical analysis
Statistical analysis was performed with SPSS 17.0 statistics, including 31 statistical variables (numerical and categorical). Time variable was calculated from the date the patient underwent coronary revascularization until January 2015, when MACE events were detected as present or absent. Normality of the variables was tested by the Shapiro- Wilk test. Differences between variables with only two categories were assessed by the non-parametric Mann-Whitney test. A p-value < 0.05 was set as statistically significant.
Results
Of 375 consecutive coronary patients, 341 patients (64.22 ± 8.90 years, 81.52% male) were included in our study. Baseline characteristics of patients are presented in Table 1.
Baseline characteristics of patients (n = 341)
Characteristics
Age (years) (mean ± SD)
64.22 ± 8.90
Male (%)
81.52
Body mass index, kg/m2
30.47 ± 7.41
Cardiovascular events (%)
- Death for cardiovascular disease
0
- Death for other causes
1.17
- Restenosis
0.9
- AVC/AIT
0.29
- Pacemaker Implant
0.87
- New By-pass
1.46
- New stent
0.87
- Heart failure
1.46
- Newly diagnosed diabetes
0.87
Ejection fraction (mean ± SD)
47.56 ± 8.8
AVC: stroke; TIA: transient ischemic attack
At T0, 52.5% of patients had undergone CABG, 43.1% PCI, and 4.4% had undergone both procedures.
At inclusion in the study, there was a high prevalence of modifiable cardiovascular risk factors (Table 1.1).
Evaluation of cardiovascular risk factors atT0 (n = 341)
Variable
%
Arteial hypertension/ medication
27.56/54.25
Body mass index > 30 kg/m2
36.07
Hypercholesterolemia / medication
59.82/94.8
Diabetes / medication
78.59/82.23
Smoking
48
Statin therapy for LDL-c control remains a pertinent therapeutic target (<xref ref-type="table" rid="t3">Table 2</xref>)
Lipid target levels and number of patients in whom these levels were reached at T1
Variable
n = 341
LDLc < 80
mg/dL
23.8 %
Non HDL < 110
mg/dL
30.8%
At T1, 76.2% of participants had LDL-c values ≥ 80 mg/dL. In fact, only 5% of revascularized patients receiving statins that reached the target LDL-c value recommended by the ESC guidelines.5,10,11
Non-HDLc or secondary lipid target and residual risk: using a non-HDL-c target < 110 mg/dL, we found that 30.8% of patients at T0 and 34.9% at T1 achieved these levels (p = NS) dL. There was no statistically significant differences between mean non-HDL-c atT0 (135.2 ± 44.95 mg/dL) and T1 (129.13 ± 40.9 mg/dL).
MACE rates and post-revascularization cardiovascular risk: the MACE rate at T2 was 7.9% in a median follow-up time of 4.33 years.
There was a positive and statistically significant association between primary lipid target of LDL-c at T1 and MACE (p = 0.039, chi test, 95% CI) (Table 3). In addition, there was a significant difference in mean non-HDL-c between the MACE categories at T1 (p = 0.02, Kruskal Wallis test, 95% CI) (Figure 2).
Relationship between LDL-c and major adverse cardiovascular events (MACE) at T1
Crosstab
Count
LDLc_T1categ
Total
.00
1.00
MACE_T2
0
225
89
314
2
2
2
4
3
0
3
3
4
1
0
1
5
1
2
3
6
5
0
5
7
2
1
3
8
2
3
5
9
3
0
3
Total
241
100
341
Chi-Square Tests
Value
df
Asymp. Sig. (2-sided)
Pearson Chi-Square
16.247a
8
.039
Likelihood Ratio
18.328
8
.019
Linear-by-Linear Association
.394
1
.530
N of Valid Cases
341
16 cells (88.9%) had expected count less than 5. The minimum expected count was 0.29
Mean LDL-c levels at T1 and major adverse cardiovascular events (MACE) rate at T2
Restenosis rate was 0.9% and was significantly influenced by average non-HDLc (p = 0.04, Mann-Whitney test, 95% CI).
The incidence of heart failure, defined by the value of ejection fraction was significantly higher in patients with increased non-HDL-c, not responsive to medications at T1 (p = 0.007, Mann-Whitney test, 95% CI).
Newly diagnosed cases of diabetes were significantly more frequent in patients with increased non-HDL-c at T1 (p = 0.017, Mann-Whitney test, 95% CI).
There was no significant difference between the incidence of MACE and the type of revascularization procedures.
Discussion
Our study demonstrates a high cardiovascular risk among coronary patients after 4.33 years of myocardial revascularization.
The drugs prescribed to be used in association with statins were platelet aggregators, beta-blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, in accordance with the ESC guidelines for secondary cardiovascular prevention.
Analysis of the relationship between the medications and achievement of target values of modifiable risk factors was previously published by our group.9 Reduction in systolic blood pressure under medication was achieved in 39.58% of subjects enrolled in this study; cardiometabolic risk was reduced under the maximum dose of statin. Although the primary lipid target was reached in only 5% of patients, better outcomes were found in the secondary lipid target, non-HDL-c.
The high metabolic risk in these coronary patients is supported by dyslipidemia and high incidence of diabetes at T1, which justifies the implementation of energetic approaches toward lifestyle changes associated with the use of proper medication in revascularized patients.
Our study did not set out to analyze the compliance of patients to post-revascularization recovery programs, which would have contributed to interpretation of our results. A low compliance to these programs and cardiovascular preventive approaches may be related to the development of atherothrombosis in coronary patients, and might explain the prevalence of cardiovascular events (7.9%) at T2 and a median survival time of 4.33 years in our study group. Further studies to evaluate the compliance of patients to these approaches would be helpful.
Our study corroborates the need for strategies to control modifiable cardiovascular risk factors.9,12,13 Despite the use of medications, patients undergoing myocardial revascularization remain at risk of cardiovascular events related to atherosclerosis progression and other metabolic diseases.9,11
Results from the EUROASPIRE IV6 pointed out that the Joint European Societies Guidelines on Cardiovascular Prevention recommendations are achieved in a still low proportion of coronary patients across Europe. In our study, only a modest percentage of revascularized coronary patients met the ESC Guidelines recommendations for LDLc -targets.10,11 Although statin was prescribed to nearly 95% of patients at T1, the LDL-c levels were not reached by most of them.
Reiner et al.13 emphasized the need to reduce LDL-c levels after a cardiovascular event to reduce coronary heart disease mortality and morbidity.13 Other authors suggested several reasons for the mediocre response during statin therapy: inadequate dose, non-adherence to prescribed dose, statin resistance and / or intolerance, and side effects.14,15 However, our results confirm the association between increased LDL-c levels with cardiovascular event rates.
We wonder if we can predict residual lipid risk in revascularized, coronary patients in use of statins. In our study group, there were significant differences in mean HDL-c and MACE rates at T2 as compared with other time points. Furthermore, they were correlated with the rate of restenosis, prevalence of heart failure and incidence of diabetes. In ESC / European Atherosclerosis Society (EAS) guidelines recommend the use of non-HDL-c as secondary target, especially among diabetic coronary patients.11,14-16 It seems that non-HDL would be a better predictor than LDLc of unstable atherosclerotic plaque.17
Reiner et al. reported that 12.2% of coronary patients in whom the LDLc target value was reached had pathological levels of non-HDL-c. In our sample, only 7.33% patients had non-HDL-c levels > 110 mg/dL and LDL-c < 80 mg/dL after myocardial revascularization.
The ESC/EAS guidelines recommend that patients with such changes in the lipid profile should be identified and treated as appropriate.18-20
Our study has some limitations. First, baseline characteristics of participants were defined in a relatively late stage of coronary artery disease, i.e. at the time of myocardial revascularization. In addition, our sample was somewhat biased, since it was composed exclusively of patients treated at Timisoara Institute of Cardiovascular Diseases, which is a specialized treatment center, and therefore, the results cannot be to all patients with coronary revascularization. However, there were relatively small differences between our results with those of previous studies conducted in Europe.16-21
Conclusions
The study highlights the need to control lipid risk factors after myocardial revascularization procedures, even at long-term, to minimize the risk of cardiovascular events in patients with coronary diseases.
Sources of Funding
This study was partially funded by Astrazeneca (Research Grants Unrestricted to the European Society of Cardiology).
Study Association
This article is part of the thesis of Doctoral submitted by Cosor Oana Catalina, from University of Medicine and Pharmacy Victor Babes Timisoara.
References1 Zengin E, Bickel C, Schnabel RB, Zeller T, Lackner KJ, Rupprecht HJ, et al; Athero Gene-Study Investigators. Risk factors of coronary artery disease in secondary prevention: results from the AtheroGene study. PLoS One. 2015;10(7):e0131434.ZenginEBickelCSchnabelRBZellerTLacknerKJRupprechtHJAthero Gene-Study InvestigatorsRisk factors of coronary artery disease in secondary prevention: results from the AtheroGene studyPLoS One2015107e01314342 Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo controlled trial. Lancet. 2004;364(9435):685-96.ColhounHMBetteridgeDJDurringtonPNHitmanGANeilHALivingstoneSJCARDS investigatorsPrimary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo controlled trialLancet200436494356856963 Knopp RH, d'Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care. 2006;29(7):1478-85.KnoppRHd'EmdenMSmildeJGPocockSJEfficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN)Diabetes Care2006297147814854 Peter S. Sever PS, Poulter NR Dahlöf B, Wedel H. Different time course for prevention of coronary and stroke events by atorvastatin in the Anglo-Scandinavian CArdiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA). Am J CArdiol. 2005;96(5A):39F-44F.PeterSPoulterNRDahlöfBWedelHDifferent time course for prevention of coronary and stroke events by atorvastatin in the Anglo-Scandinavian CArdiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA)Am J CArdiol2005965A39F44F5 Piepoli MF, Hoes AW, Agerwall S, Albus C, Brotons C, Catapano AL, et al; Authors/Task Force Members. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315-81.PiepoliMFHoesAWAgerwallSAlbusCBrotonsCCatapanoALAuthors/Task Force Members2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR)Eur Heart J20163729231523816 Kotseva K, Wood D, De Bacquer D, De Backer G, Rydén L, Jennings C, et al; EUROASPIRE Investigators. EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. Eur J Prev Cardiol. 2016;23(6):636-48.KotsevaKWoodDDe BacquerDDe BackerGRydénLJenningsCEUROASPIRE InvestigatorsEUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countriesEur J Prev Cardiol20162366366487 Kotseva K, Wood D, De Backer G, De Bacquer D, Pyörälä K, Keil U; EUROASPIRE Study Group. EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries. Eur J Cardiovasc Prev Rehabil. 2009;16(2):121-37.KotsevaKWoodDDe BackerGDe BacquerDPyöräläKKeilUEUROASPIRE Study GroupEUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countriesEur J Cardiovasc Prev Rehabil20091621211378 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-421.National Cholesterol Education ProgramThird Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final reportCirculation200210625314334219 Cosor OC, Baibata DE, Iurciuc S, Velimirovici D, Duda-Seiman D, et al. Cardiovascular risk profile of remote process of coronary dezobstruction. In: Center of Promoting Health Education and Motivation for Prevention in Dentistry Center for Continuous Medical Education.Timisoara: WALDPRESS: 2016. (Medicine in Evolution volume XXII, nº3).CosorOCBaibataDEIurciucSVelimiroviciDDuda-SeimanDCardiovascular risk profile of remote process of coronary dezobstructionCenter of Promoting Health Education and Motivation for Prevention in Dentistry Center for Continuous Medical EducationTimisoaraWALDPRESS2016(Medicine in Evolution volume XXII, nº3)10 Perk J, De Backer G, Gohlek H, Graham I, Reiner Z, Verschuren WM, et al; Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice.; European Association for Cardiovascular Prevention and Rehabilitation. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Atherosclerosis. 2012;223(1):1-68.PerkJDe BackerGGohlekHGrahamIReinerZVerschurenWMFifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice.; European Association for Cardiovascular Prevention and Rehabilitation. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts)Atherosclerosis2012223116811 Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al; ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS guidelines for the management of dyslipidemias: the task force for the management of dyslipidemias of European Society of Cardiology (ESC) and the European Atherosclerosis Society ( EAS). Eur Heart J. 2011;32(14):1769-818.ReinerZCatapanoALDe BackerGGrahamITaskinenMRWiklundOESC Committee for Practice Guidelines 2008-2010 and 2010-2012 CommitteesESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS guidelines for the management of dyslipidemias: the task force for the management of dyslipidemias of European Society of Cardiology (ESC) and the European Atherosclerosis Society ( EAS)Eur Heart J201132141769181812 EUROASPIRE. A European Society of Cardiology survey of secondary prevention of coronary heart disease: principal results. EUROASPIRE Study Group. European Action on Secondary Prevention through Intervention to Reduce Events. Eur Heart J. 1997;18(10):1569-82. Erratum in: Eur Heart J. 1998;19(2):356-7EUROASPIREA European Society of Cardiology survey of secondary prevention of coronary heart disease: principal results. EUROASPIRE Study Group. European Action on Secondary Prevention through Intervention to Reduce EventEur Heart J1997181015691582Erratum in: Eur Heart J. 1998;19(2):356-713 Reiner Z, De Backer G, Fras Z, Kotseva K, Tokgözoglu L, Wood D. EUROASPIRE Investigators. Lipid lowering drug therapy in patients with coronary heart disease from 24 European countries--Findings from the EUROASPIRE IV survey. Atherosclerosis. 2016;246:243-50.ReinerZDe BackerGFrasZKotsevaKTokgözogluLWoodDLipid lowering drug therapy in patients with coronary heart disease from 24 European countries--Findings from the EUROASPIRE IV surveyAtherosclerosis201624624325014 Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA. 2012;307(12):1302-9. Erratum in: JAMA. 2012;307(18):1915.BoekholdtSMArsenaultBJMoraSPedersenTRLaRosaJCNestelPJAssociation of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysisJAMA20123071213021309Erratum in: JAMA. 2012;307(18):191515 Zambon A, Puato M, Faggin E, Grego F, Rattazzi M, Pauletto P. Lipoprotein remnants and dense LDL are associated with features of unstable carotid plaque: a flag for non-HDL-C. Atherosclerosis. 2013;230(1):106-9.ZambonAPuatoMFagginEGregoFRattazziMPaulettoPLipoprotein remnants and dense LDL are associated with features of unstable carotid plaque: a flag for non-HDL-CAtherosclerosis2013230110610916 Widimský P, Zvárová J, Monhart Z, Janský P; ALERT-CZ Investigators. The use of revascularization strategies in patients with acute coronary syndromes admitted to hospitals without catheterization facilities: Results from the ALERT-CZ registry. Cor et Vasa. 2013;55(3):e207-11.WidimskýPZvárováJMonhartZJanskýPALERT-CZ InvestigatorsThe use of revascularization strategies in patients with acute coronary syndromes admitted to hospitals without catheterization facilities: Results from the ALERT-CZ registryCor et Vasa2013553e207e21117 Gyberg V, De Bacquer D, De Backer G, Jennings C, Kotseva K, Mellbin L, et al; EUROASPIRE Investigators. Patients with coronary artery disease and diabetes need improved management: a report from the EUROASPIRE IV survey: a registry from the EuroObservational Research Programme of the European Society of Cardiology. Cardiovasc Diabetol. 2015;14:133.GybergVDe BacquerDDe BackerGJenningsCKotsevaKMellbinLEUROASPIRE InvestigatorsPatients with coronary artery disease and diabetes need improved management: a report from the EUROASPIRE IV survey: a registry from the EuroObservational Research Programme of the European Society of CardiologyCardiovasc Diabetol20151413318 Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB Sr, Gibbons R, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2935-59. Erratum in: J Am Coll Cardiol. 2014;63(25 Pt B):3026.GoffDCJrLloyd-JonesDMBennettGCoadySD'AgostinoRBSrGibbonsRAmerican College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/ American Heart Association Task Force on Practice GuidelinesJ Am Coll Cardiol20146325Pt B29352959Erratum in: J Am Coll Cardiol. 2014;63(25 Pt B):302619 Rabar S, Harker M, O'Flynn N, Wierzbicki AS, Guideline Development Group. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance. BMJ. 2014;349:g4356.RabarSHarkerMO'FlynnNWierzbickiASGuideline Development GroupLipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidanceBMJ2014349g435620 Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, et al. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet. 2015;385(9984):2264-71.MegaJLStitzielNOSmithJGChasmanDICaulfieldMJDevlinJJGenetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trialsLancet201538599842264227121 JBS3 Board. Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart. 2014;100 Suppl 2:ii1-ii67.JBS3 BoardJoint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3)Heart2014100Suppl 2ii1ii67Artigos OriginaisFatores Lipídicos de Risco Cardiovascular e Taxa de Eventos Cardiovasculares após Revascularização MiocárdicaCatalinaCosor Oana1AdinaBucur1SmaranditaBaibata Emilia Dana1AngelaDragomir2DanGaita1SilviaMancas1University of Medicine and Pharmacy Victor Babes Timisoara - RomaniaThe Institute of Cardiovascular Disease Timisoara - RomaniaCorrespondência: Cosor Oana Catalina. Str.Arh.V.Vlad,bl 13 ,sc D,ap 2 - 13. Postal Code 035332, Timisoara, Romênia. E-mail: andrei.csr@gmail.com
Contribuição dos autores
Concepção e desenho da pesquisa: Catalina CO, Silvia M. Obtenção de dados: Catalina CO, Smarandita BED. Análise e interpretação dos dados: Catalina CO, Adina B. Análise estatística: Angela D. Obtenção de financiamento: Dan G. Redação do manuscrito: Catalina CO, Silvia M. Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Dan G, Silvia M.
Potencial Conflito de Interesse
Declaro não haver conflito de interesses pertinentes.
ResumoFundamentos:
A doença arterial coronariana é um problema de saúde pública, e principal causa de morte prematura na Europa e no mundo. Há evidência epidemiológica de que o controle dos fatores de risco cardiovasculares após a revascularização do miocárdio encontra-se ainda abaixo do desejável.
Objetivo:
Analisar a incidência de eventos cardiovasculares em pacientes em tratamento para prevenção secundária após revascularização do miocárdio.
Método:
Estudo unicêntrico com pacientes com doença coronariana consecutivos, identificados retrospectivamente. O estudo foi conduzido no Instituto de Doenças Cardiovasculares em Timisoara, Romênia. Os pacientes com diagnóstico de revascularização por doença arterial coronariana (intervenção coronária percutânea, ICP ou ponte de artéria coronária, CABG) foram incluídos, seguindo-se os critérios de inclusão do estudo EUROASPIRE IV. Os dados foram analisados em três momentos - T0, quando a revascularização do miocárdio foi realizada; T1 (entrevista com pacientes submetidos à revascularização há mais de 6 meses e menos de 5 anos); e T2 (entrevista com pacientes submetidos à revascularização há mais de 5 anos).
Resultados:
Dos 375 pacientes com doença coronariana, 341 foram incluídos no estudo. No T1, somente 5% e 34,9% dos pacientes atingiram os níveis desejáveis de LDL-c e não-HDL-c, respectivamente. A taxa de MACE em T2 foi de 7,9% em um tempo de acompanhamento mediano de 4,33 anos. Encontramos uma associação significativa positiva entre taxa de MACE e LDL-c em T1 (p = 0,039). Houve diferenças significativas nos níveis médios de não-HDL-c entre as categorias de MACE em T1 (p = 0,02). Valores médios de não-HDL associaram-se significativamente com a incidência de insuficiência cardíaca (p = 0,007), diabetes com diagnóstico recente (p = 0,017) e taxa de reestenose (p = 0,04).
Conclusão:
O estudo destaca a necessidade de se controlar fatores de risco relacionados ao perfil lipídico após procedimentos de revascularização do miocárdio, mesmo em longo prazo, a fim de minimizar o risco de eventos cardiovasculares em pacientes com doenças coronarianas.
Doença da Artéria CoronarianaFatores de RiscoLipídeosMetabolismoRevascularização MiocárdicaEpidemiologiaIntrodução
Apesar dos avanços na área, a doença arterial coronariana ainda é considerada "o flagelo do mundo moderno" e problema de saúde pública. É a principal causa de morte prematura na Europa e no mundo.
Neste estudo, nosso foco foi entender a evolução do processo aterotrombótico em pacientes com doença coronária sintomáticos, submetidos previamente à revascularização da artéria coronária: intervenção coronária percutânea (ICP) ou ponte de artéria coronária (CABG).1
A relação entre colesterol LDL (LDL-c) e a incidência de eventos cardiovasculares foi demonstrada por vários estudos epidemiológicos: CARDS2 ASPEN3 ASCOT.4 As novas diretrizes da Sociedade Europeia de Cardiologia (SEC) para prevenção de doença cardiovascular recomendaram um nível máximo de 70 mg/dL para colesterol de lipoproteína de baixa densidade (LDL-c) para pacientes com risco alto ou muito alto.5 Além disso, pacientes em tratamento com estatinas também podem apresentar risco muito alto para doenças cardiovasculares.5,6
Os estudos EUROASPIRE III e IV representam a evidência epidemiológica de que o controle de fatores de risco cardiovasculares modificáveis em pacientes com doença coronariana encontra-se ainda aquém do desejável.6,7
A hipótese de nosso estudo foi que um controle ineficaz dos fatores de risco cardiovasculares tem um efeito de longo prazo sobre a incidência de eventos cardiovasculares fatais e não fatais. O objetivo de nosso estudo foi avaliar a incidência de eventos cardiovasculares fatais e não fatais em pacientes com doença coronariana em tratamento com estatinas anos após revascularização da artéria coronária, seguindo os critérios do Programa de Prevenção de Doença Cardiovascular da SEC.5
Métodos
Este é um estudo unicêntrico realizado no Instituto de Doenças Cardiovasculares de Timisoara, Romênia. Os critérios de inclusão seguiram o protocolo do estudo EuroAspire IV. Um total de 375 pacientes com doença coronariana consecutivos, com idade entre 18 e 80 anos e diagnóstico definitivo de revascularização por doença arterial coronariana (ICP, CABG) foram identificados retrospectivamente. Desses, 341 foram considerados elegíveis e 341 foram incluídos no estudo (Figura 1). Dados clínicos dos pacientes foram avaliados em três momentos - T0, quando a realização de revascularização com sucesso foi identificada; T1 (de 6 meses a 3 anos após revascularização do miocárdio), e T2 (de 3 a 5 anos após revascularização do miocárdio).
Delineamento do estudo; ACTP: angioplastia coronária transluminal percutânea; CABG: ponte de artéria coronária
Os seguintes dados foram coletados a partir de um banco de dados eletrônico: dados de perfil lipídico - colesterol total (CT); triglicerídeos (TG); colesterol de lipoproteína de alta densidade (HDL-c); LDL-c; não-HDL, calculado subtraindo-se HDL-c do CT8 - número de eventos cardiovasculares fatais e não fatais, eventos cardiovasculares adversos importantes (MACE - major adverse cardiovascular events) - morte por doença cardiovascular, morte por outras causas, acidente vascular cerebral (AVC)/ ataque isquêmico transitório (AIT), estimulação elétrica por marca-passo, hospitalização para reintervenção - angioplastia coronária transluminal percutânea (ACTP) ou CABG, hospitalização por insuficiência cardíaca, diagnóstico de diabetes mellitus. O risco lipídico foi avaliado em T0 e T1, seguindo os critérios de prevenção da SEC.5 A taxa de eventos cardiovasculares fatais e não fatais foi analisada com base no risco lipídico potencial.
O acompanhamento dos pacientes foi realizado por um questionário validado para países que participaram do estudo EUROASPIRE IV.6 Na inclusão no estudo, usamos os protocolos pós-revascularização especificados nas diretrizes da SEC para prevenção secundária de doenças cardiovasculares (2012),9 adotadas pela Sociedade Romena de Cardiologia.
Análise estatística
A análise estatística foi realizada pelo programa SPSS 17.0, incluindo 31 variáveis (numéricas e categóricas). A variável "tempo" foi calculada como a diferença entre a data em que o paciente foi submetido à revascularização à janeiro de 2015, quando eventos MACE foram detectados como "presentes" ou "ausentes". A normalidade das variáveis foi testada pelo teste de Shapiro-Wilk. Diferenças entre variáveis com somente duas categorias foram avaliadas pelo teste não paramétrico de Mann-Whitney. Um valor de p < 0.05 foi considerado como estatisticamente significativo.
Resultados
Dos 375 pacientes consecutivos com doença coronariana, 341 (64,22 ± 8,90 anos, 81,52 % homens) foram incluídos no estudo. Características basais dos pacientes estão apresentadas na Tabela 1.
Em T0, 52,5% dos paciets haviam sido submetidos à CABG, 43.1% à ICP, e 4,4% a ambos os procedimentos. Na inclusão no estudo, havia uma alta prevalência de fatores de risco cardiovasculares modificáveis (Tabela 1.1).
Avaliação dos fatores de risco cardiovascular em T0 (n = 341)
Variável
%
Hipertensão arterial/medicamento
27,56/54,25
Índice de Massa Corporal > 30 kg/m2
36,07
Hipercolesterolemia / medicamento
59,82/94,8
Diabetes / medicamento
78,59/82,23
Tabagismo
48
Controle de LDL-c com uso de estatinas permanece uma abordagem pertinente (<xref ref-type="table" rid="t7">Tabela 2</xref>)
Níveis lipídicos desejáveis e número de pacientes em que esses níveis foram alcançados em T1
Variável
n = 341
LDL-c < 80
mg/dL
23,8%
Não HDL-c < 110
mg/dL
30,8%
Em T1, 76,2% dos participantes tinham valores de LDL-c ≥ 80 mg/dL. Somente 5% dos pacientes submetidos à revascularização e em uso de estatinas alcançaram os valores de LDL-c recomendados pela SEC.5,10,11
Limite desejável de não-HDL-c (alvo secundário para prevenção de doença cardiovascular e risco residual: utilizando um limite desejável de níveis de não-HDL-c < 110 mg/dL, observamos que 30,8% dos pacientes no T0 e 34,9% dos pacientes em T1 atingiram esses níveis (p = ns). Não foi encontrada diferença estatisticamente significativa entre os valores médios de não-HDL em T0 (135,2 ± 44,95 mg/dL) em T1 (129,13 ± 40,9 mg/dL).
Taxas de MACE e risco cardiovascular pós-revascularização: a taxa de MACE em T2 foi de 7,9% em um tempo de acompanhamento mediano de 4,33 anos.
Houve uma associação significativa positiva entre alvo primário de prevenção (LDL-c) em T1 e MACE (p = 0,039, teste do qui-quadrado, IC 95%) (Tabela 3). Além disso, houve uma diferença significativa nos valores médios de HDL-c entre as categorias de MACE em T1 (p = 0,02, teste de Kruskal Wallis, IC 95%) (Figura 2).
Relação entre LDL-c e taxa de eventos cardiovasculares adversos importantes (MACE) em T1
Tabela de contingência
Valores
LDLc_T1categ
Total
.00
1.00
MACE_T2
0
225
89
314
2
2
2
4
3
0
3
3
4
1
0
1
5
1
2
3
6
5
0
5
7
2
1
3
8
2
3
5
9
3
0
3
Total
241
100
341
Testes de qui-quadrado
Valor
df
Asymp. Sig. (2-sided)
Qui-quadrado de Pearson
16.247a
8
.039
Razão de verossimilhança
18.328
8
.019
Associação linear
.394
1
.530
No de casos válidos
341
16 células (88.9%) tiveram valor esperado < 5. O valor mínimo esperado foi 0,29.
Valores médios de HDL-c em T1 e taxa de eventos cardiovasculares adversos importantes (MACE) em T2
A taxa de reestenose foi de 0,9%, a qual foi significativamente influenciada por não-HDL-c médio (p = 0,04, teste de Mann-Whitney, IC 95%).
A incidência de insuficiência cardíaca, definida pelo valor de fração de ejeção foi significativamente maior em pacientes com níveis de não-HDL-c elevados, apesar do uso de estatinas, em T1 (p = 0,007, teste de Mann-Whitney, IC95%).
Casos recentemente diagnosticados de diabetes foram significativamente mais frequentes em pacientes com níveis aumentados de não-HDL-c no T1 (p = 0,017, teste de Mann-Whitney, IC95%).
Não houve diferença significativa entre a incidência de MACE e no tipo de procedimentos de revascularização.
Discussão
Nosso estudo demonstra um risco cardiovascular em paciente com doença coronariana após 4,33 anos de revascularização do miocárdio.
Os medicamentos prescritos em associação com estatinas foram agregantes plaquetários, betabloqueadores, inibidores da enzima de conversão da angiotensina e bloqueadores do receptor de angiotensina II, de acordo com as diretrizes da SEC para prevenção secundária de doença cardiovascular.
A análise da relação entre o uso de medicamentos e o alcance dos valores desejáveis dos fatores de risco modificáveis foram publicados por nosso grupo anteriormente.9 Redução da pressão sanguínea por medicamento foi observado em 39,6% dos pacientes incluídos no presente estudo; risco cardiometabólico foi reduzido com o uso de dose máxima de estatina. Apesar de os níveis desejados de LDL haverem sido alcançados em apenas 5% dos pacientes, melhores resultados foram observados nos níveis de não-HDL-c.
O elevado risco metabólico nesses pacientes com doença coronária é corroborado pela presença de dislipidemia e alta incidência de diabetes em T1, o que justifica a implementação de medidas energéticas que objetivem mudanças de estilo de vida associado ao uso de medicamentos apropriados em pacientes submetidos à revascularização.
Em nosso estudo, não foi avaliada a adesão dos pacientes a programas de recuperação pós-revascularização, o que contribuiria à interpretação de nossos resultados. Uma baixa adesão a esses programas e a abordagens de prevenção a eventos cardiovasculares pode estar relacionada ao desenvolvimento de aterotrombose nesses pacientes, e pode explicar a taxa de eventos (7,9%) em T2 e tempo de sobrevida mediana de 4,33 anos em nossos pacientes. Seria interessante que outros estudos que avaliassem a adesão dos pacientes a essas abordagens fossem realizados.
Nosso estudo reforça a necessidade de estratégias para controlar fatores de risco cardiovasculares modificáveis.9,12,13 Apesar do uso de medicamentos, pacientes submetidos à revascularização do miocárdio permanecem em riso de eventos cardiovasculares relacionados à progressão de aterosclerose e doenças metabólicas.9,11
Resultados do estudo EUROASPIRE IV6 destaca que as recomendações das Diretrizes das Sociedades Europeias para Prevenção Cardiovascular (Joint European Societies Guidelines on Cardiovascular Prevention) são seguidas em uma pequena parcela dos pacientes com doença coronária na Europa. Em nosso estudo, apenas uma pequena porcentagem dos pacientes atingiram as recomendações da ESC para os níveis de LDL-c.10,11 Apesar de as estatinas estarem prescritas a quase 95% dos pacientes em T1, os níveis desejáveis de LDL-c não foram alcançados por sua maioria.
Reiner et al.13 enfatizaram a necessidade de se reduzir os níveis de LDL-c após ocorrência de evento cardiovascular para reduzir mortalidade e morbidade de doenças cardiovasculares.13 Outros sugeriram várias razões pela baixa resposta durante o tratamento com estatinas - dose inadequada, não adesão à dose prescrita, resistência e/ou intolerância à estatina, e efeitos colaterais.14,15 Contudo, nossos resultados confirmaram a associação entre níveis aumentados de LDL-c com taxas de eventos cardiovasculares.
Gostaríamos de saber se é possível predizer o risco residual relacionado ao perfil lipídico em pacientes com doença coronariana, submetidos à revascularização em uso de estatinas. Foram observadas diferenças significativas nos valores médios de HDL-c e taxas de MACE em T2 comparado a T0 e T1. Além disso, ambos correlacionaram-se à taxa de reestenose, prevalência de insuficiência cardíaca e incidência de diabetes. As diretrizes da SEC e Sociedade Europeia de Aterosclerose (SEA) recomendam o uso do não-HDL-c como alvo secundário, especialmente em pacientes com doença coronariana e diabetes mellitus.11,14-16 Parece que o não-HDL-c seria um melhor preditor que o LDL-c na formação de placa aterosclerótica instável.17
Reiner et al. relataram que 12.2% dos pacientes em que os valores desejáveis de LDL-c foram atingidos apresentaram níveis elevados de não-HDL-c. Em nossa amostra, 7,33% dos pacientes apresentavam níveis de HDL-c > 110 mg/dL e LDL-c<80 mg/dL após revascularização do miocárdio.
As diretrizes da SEC e SEA recomendam que pacientes com tais mudanças no perfil lipídico devem ser identificados e tratados quando necessário.18-20
Nosso estudo tem algumas limitações. Primeiro, as características basais dos participantes foram definidos em um estágio relativamente tardio da doença arterial coronariana, i.e., somente no momento de revascularização do miocárdio. Além disso, é possível que haja ocorrido um viés na seleção da amostra, uma vez que somente pacientes tratados no Instituto de Doenças Cardiovasculares de Timisoara foram incluídos. O instituto é um centro especializado e, portanto, os resultados não podem ser generalizados a todos os pacientes com revascularização do miocárdio prévia. Contudo, observamos diferenças relativamente pequenas entre nossos resultados e aqueles encontrados em outros estudos europeus anteriores.16-21
Conclusões
O estudo destaca a necessidade de se controlar fatores de risco relacionados ao perfil lipídico após procedimentos de revascularização do miocárdio, mesmo em longo prazo, a fim de minimizar o risco de eventos cardiovasculares em pacientes com doenças coronarianas.
Fontes de Financiamento
O presente estudo foi parcialmente financiado por Astrazeneca (Bolsas de Pesquisa Irrestritas para a Sociedade Europeia de Cardiologia).
Vinculação Acadêmica
Este artigo é parte de tese de Doutorado de Cosor Oana Catalina pela University of Medicine and Pharmacy Victor Babes Timisoara.