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ORIGINAL RESERCH

Antiplatelet Therapy for Secondary Prevention After Myocardial Infarction in Antiplatelet-Naive High Cardiovascular Risk Patients with Non-Obstructive Coronary Artery Disease
Ioseb Sikharulidze,1 Kakhaber Chelidze,2,ID Merab Mamatsashvili,3 Levan Chelidze,2,ID Tamar Kajaia,2  Irma Bakhlishvili4
ABSTRACT
The growing evidence indicates the importance of non-obstructive coronary artery disease (NOCAD), with a high risk of MACEs. The relevance of antiplatelet therapy is high and depends on the type of MINOCA. However, the effectiveness of different antiplatelet treatment regimens and secondary prevention strategies for patients with non-obstructive coronary artery disease is still unclear. In our previous cohort study, we found that secondary prevention with dual antiplatelet therapy with aspirin and P2Y12 receptor antagonist clopidogrel in patients with NOCAD was not significantly effective than aspirin alone in reducing 1-year MACEs. Because the development and validation cohorts of patients with NOCAD were heterogeneous in terms of cardiovascular risk, in the current study we aimed to compare the preventive effect of DAPT with aspirin alone in high cardiovascular-risk patients. Following the aim of our study, we selected 15 of 55 MINOCA patients with a high 10-year risk for ASCVD (≥20%) from the DAPT group and 19 of 60 patients with the same risk from the no-DAPT group. The results of our previous and present studies corroborate previously published data. DAPT had no secondary preventive effect on one-year MACE in MINOCA patients with different cardiovascular risks. The use of DAPT in patients with MINOCA is a topic for discussion and requires further investigations with a long-term follow-up period.

DOI: 10.52340/GBMN.2023.01.01.08
BACKGROUND
The majority of current therapeutic strategies for coronary artery disease (CAD) are based on the historical paradigm of elimination of coronary artery obstructive plaque. (1) However, the growing evidence indicates the clinical importance of non-obstructive coronary artery disease, which is associated with a high risk of future major adverse cardiovascular events (MACEs). (2-5)
 
The vulnerability of the non-obstructive plaque with erosion and subsequent thrombosis is a major pathological substrate of NOCAD-associated MACEs. (6-10) Therefore, the relevance of antiplatelet therapy is high in patients with NOCAD. However, the effectiveness of different antiplatelet treatment regimens and secondary prevention strategies for patients with non-obstructive coronary artery disease is uncertain. (11)
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Lindahl B et al. reported a neutral benefit for dual antiplatelet therapy in patients with myocardial infarction with non-obstructive coronary artery (MINOCA) disease. (12)

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The ongoing multicenter, prospective, randomized, controlled, and open-label registry-based trial MINOCA-BAT will be answering the question about the usefulness of DAPT in MINOCA patients. (13,14) 

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In our previous cohort study, we found that secondary prevention with dual antiplatelet therapy with aspirin and P2Y12 receptor antagonist clopidogrel in patients with non-obstructive coronary disease was not significantly effective than aspirin alone for reducing 1-year MACEs. (15) Because the development and validation cohorts of patients with NOCAD were heterogeneous in terms of cardiovascular risk, in the current study, we aimed to compare the preventive effect of DAPT with aspirin alone in high cardiovascular-risk patients.

METHODS
Patient population
Overall, 115 of 1018 antiplatelet-naïve patients admitted to the Coronary Care Unit of Tsinamdzgvrishvili Center of Cardiology LTD (Tbilisi, Georgia) and classified as MINOCA were included in the study between March 2018 and Aug 2019. The study population was initially divided into two groups: 55 patients with MINOCA were distributed into the cohort of DAPT (aspirin + clopidogrel), and 60 patients with MIINOCA - into the cohort of No-DAPT (aspirin alone). The control group consisted of 50 patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) with obstructive coronary disease. Following the aim of our study, we selected 15 MINOCA patients with a high 10-year risk for ASCVD (≥20%) from the DAPT group and 19 patients with the same risk from the no-DAPT group. The study protocol was reviewed and approved by the Ethic Committees of Tbilisi State Medical University and Tsinamdzgvrishvili Center of Cardiology LTD, and written informed consent was provided by each study participant. 
 
Table 1 depicts the baseline characteristics of patients with a high 10-year risk for ASCVD.​
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Diagnosis of MINOCA
The criteria for MINOCA were a universal definition for MI with non-obstructive coronary arteries on angiography (<50% stenosis) and no specific clinically evident cause for the acute coronary syndrome. (16-19) 
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Cardiovascular risk estimation
For the prediction over 10 years of risk of myocardial infarction, stroke, or cardiovascular death, atherosclerotic cardiovascular disease (ASCVD) Risk Estimator Plus was used (intended for people between the ages of 40 and 79). (20)
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Bleeding risk estimation
For the stratification post-MI major bleeding risk CRUSADE score calculator was used with following interpretation: (21)

  • Score ≤20 - very low risk (3.1%) of major bleeding;

  • Score 21-30 - low risk (5.5%) of major bleeding;

  • Score 31-40 - moderate risk (8.5%) of major bleeding;

  • Score 41-50 - high risk (11.9%) of major bleeding;

  • Score >50 - very high risk (19.5%) of major bleeding.

 

​Statistical analysis

IBM SPSS version 26.0 (IBM Corp., Armonk, NY, USA) was used for analyzing data. The differences between development and validation cohorts had assessed by the nonparametric Mann-Whitney U test, descriptive statistics, linear regression analysis, Pearson correlation, ANOVA test, Z-scores, and B coefficients were used for the statistical analysis of variables. A statistical significance was taken as a 2-tailed p<0.05.
RESULTS
Patient characteristics
The mean age of the non-DAPT group patients was statistically higher compared to DAPT group patients (67.58±1.84 vs. 65.8±0.77, p<0.0001. There were no significant differences in terms of the female gender, body mass index, smoking status, arterial hypertension, type 2 diabetes mellitus, left ventricular ejection fraction (EF), history of atrial fibrillation, comorbidity with COPD, dyslipidemia, glomerular filtration rate, highly sensitive C-reactive protein concentration, the extent of coronary artery disease, 10-year cardiovascular and bleeding risk, and baseline treatment between the development and validation cohorts. Neither previous revascularization nor a history of major bleeding and ongoing atrial fibrillation was in the comparator groups (Tab.1).

TABLE 1. Baseline characteristics of MINOCA patients with a high 10-year risk for ASCVD​
Antiplatelet Therapy for Secondary Prevention After Myocardial Infarction in Antiplatelet-Naive High Cardiovascular Risk Patients with Non-Obstructive Coronary Artery Disease
Abbreviations: ACIs: Angiotensin-converting enzyme inhibitors; AF: Atrial fibrillation; ARBs: Angiotensin receptor blockers; ASCVD: Atherosclerotic cardiovascular disease; BB: Beta-blockers; BMI: Body mass index; CCB: Calcium channel blockers; EF: Left ventricle ejection fraction; GFR: Glomerular filtration rate; HDL-C: high-density lipoprotein cholesterol; hs-CRP: Highly sensitive C-reactive protein; M±SD: mean ± standard deviation; NOCAD: Non-obstructive coronary artery disease; TC: Total cholesterol.
 
One-year MACEs
The one-year MACEs, such as all-cause death, myocardial infarction (MI), stroke, hospitalization because of heart failure, revascularization, and atrial fibrillation are presented in Table 2.

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TABLE 2. Univariate comparison of one-year MACEs and minor bleeding by groups

Univariate comparison of one-year MACEs and minor bleeding by groups
The association of baseline predictors with separate components of major cardiovascular events
The unique contribution of the baseline indices in the predictions of each constituent of MACEs was assessed by the multivariate regression analysis. Table 3 presents all statistically significant associations.

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TABLE 3. Multiple linear regression analysis coefficients of significant correlation between baseline indices and separate components of MACEs

Antiplatelet Therapy for Secondary Prevention After Myocardial Infarction in Antiplatelet-Naive High Cardiovascular Risk Patients with Non-Obstructive Coronary Artery Disease
Abbreviations: ASCVD: Atherosclerotic cardiovascular disease; BB: beta-blockers; BMI: body mass index; CI: confidential interval; COPD: chronic obstructive pulmonary disease.
 
By the multivariate linear regression analysis, a positive predictive correlation was seen between all-cause mortality and the history of chronic obstructive pulmonary disease (COPD). A statistically significant association also was revealed between myocardial infarction (MI) and two predictors: a positive correlation in the case of a 10-year atherosclerotic cardiovascular disease (ASCVD) score and a negative in the case of previous use of beta-blockers. The predictor for revascularization was the age of patients.
DISCUSSION

The underlying etiology of MINOCA is heterogenous and the effectiveness of DAPT is unclear. (22) Dual anti-aggregation might be appropriate in case of plaque disruption, coronary embolism, coronary dissection, or hypercoagulability because of thrombophilia, (23,24) and ineffective in such cases as Takotsubo cardiomyopathy, myocarditis, epicardial coronary spasm, etc. (23,25)

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In the observational study of the SWEDEHEART registry, 66.4% of patients with MINOCA were treated with DAPT with the null effect on 1-year MACE. (12)

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In the study conducted by Paolisso et al. treatment with DAPT was not associated with a reduction in MACE or all-cause death in patients with MINOCA. (26)

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Gilberti et al. investigated 621 patients with MINOCA with DAPT in 58.8% of cases. The treatment was not associated with a reduction of all-cause mortality, stroke, or heart failure hospitalization. (27)  

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Treatment with DAPT was not associated with a reduction of MACE in the study conducted by Abdu et al. (28)

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The results of our previous (15) and present studies corroborate previously published data. DAPT had no secondary preventive effect on one-year MACE in MINOCA patients with different cardiovascular risks.

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It is logical, that high ASCVD risk and previous beta-blocker use are independent predictors of myocardial infarction on multivariable analysis. The same can be said of the correlation between the age of patients with late revascularization procedures. However, it is interesting, that the predictor of all-cause mortality was the comorbidity with COPD rather than traditional cardiovascular risk factors.

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The main limitation of the present study is that it was single-center observational research with limited sample size. In addition, we did not differentiate patients with MINOCA type, and only clopidogrel was used in combination with aspirin.

CONCLUSIONS

The use of DAPT in patients with MINOCA is a topic for discussion and requires further investigations with a long-term follow-up period.  

AUTHOR AFFILIATION

1 Batumi Center for Cardiovascular Diseases and Interventional Medicine, Ckubuc "MedCenter" LTD, Batumi, Georgia;

2 Department of Internal Medicine, Tbilisi State Medical University (TSMU), Tbilisi, Georgia;

3 Angio-cardiology Clinic LTD “Adapti” LTD, Tbilisi, Georgia;

4 Department of Interventional Cardiology & Cardio Surgery, LTD Tbilisi Heart Center, Tbilisi, Georgia.

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ACKNOWLEDGEMENTS

Special thanks to Prof. Bezhan Tsinamdzgrishvili M.D., Ph.D. head of Tsinamdzgvrishvili Center of Cardiology LTD for his support during the present study.

REFERENCES

  1. Marc R. Dweck, David E. Newby. Non-obstructive coronary artery disease can no longer be ignored. European Heart Journal - Cardiovascular Imaging (2020) 21, 489–490 doi:10.1093/ehjci/jeaa022

  2. Douglas PS, Hoffmann U, Patel MR, Mark DB, Al-Khalid HR, Cavanaugh B et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med 2015;372:1291–300.

  3. SCOT-HEART Investigators, Newby DE, Adamson PD, Berry C, Boon NA, Dweck MR et al. Coronary CT angiography and 5-year risk of myocardial infarction. N Engl J Med 2018;379:924–33.

  4. Williams MC, Moss AJ, Dweck M, Adamson PD, Alam S, Hunter A et al. Coronary artery plaque characteristics associated with adverse outcomes in the SCOT-HEART study. J Am Coll Cardiol 2019;73:291–301.

  5. Ferencik M, Mayrhofer T, Bittner DO, Emami H, Puchner SB, Lu MT et al. Use of high-risk coronary atherosclerotic plaque detection for risk stratification of patients with stable chest pain: a secondary analysis of the PROMISE randomized clinical trial. JAMA Cardiol 2018;3:144–52.

  6. Carl J. Pepine, MD; Keith C. Ferdinand, MD; Leslee J. Shaw, PHD; Kelly Ann Light-McGroary, MD; Rashmee U. Shah, MD, MS; Martha Gulati, MD, MS; Claire Duvernoy, MD; Mary Norine Walsh, MD; C. Noel Bairey Merz, MD. Emergence of Nonobstructive Coronary Artery Disease. A Women’s Problem and Need for Change in Definition on Angiography. J Am Coll Cardiol. 2015;66(17):1918-1933.

  7. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 2012;33:734–44.

  8. Maddox TM, Stanislawski M, Grunwald G, et al. non-obstructive coronary artery disease is not benign: Insights from the VA CART program on the association between non-obstructive disease and cardiac events (abstr). Circ Cardiovasc Qual Outcomes 2014;7:A24.

  9. Min JK, Dunning A, Lin FY, et al., for the CONFIRM Investigators. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 2011;58:849–60.

  10. Hulten EA, Carbonaro S, Petrillo SP, Mitchell JD, Villines TC. Prognostic value of cardiac computed tomography angiography: a systematic review and meta-analysis. Journal of the American College of Cardiology. 2011; 57(10):1237–47. doi: 10.1016/j.jacc.2010.10.011 PMID: 21145688.

  11. Wenjie Chen, Yufeng Jiang, Tan Chen, Yafeng Zhou. Antiplatelet therapy in patients with myocardial infarction with non-obstructive coronary arteries: A clinical perspective. Front Cardiovasc Med. 2022; 9: 1081934. doi: 10.3389/fcvm.2022.1081934.

  12. Lindahl B, Baron T, Erlinge D, et al. Medical therapy for secondary prevention and long-term outcome in patients with myocardial infarction with non-obstructive coronary artery (MINOCA) disease. Circulation. 2017;135:1481---9.

  13. Gabriella Passacquale, Pankaj Sharma, Divaka Perera, Albert Ferro. Antiplatelet therapy in cardiovascular disease: Current status and future directions. Br J Clin Pharmacol.2022;88:2686–2699 https://doi.org/10.1111/bcp.15221

  14. Anna M Nordenskjöld, Stefan Agewall, Dan Atar, Tomasz Baron, John Beltrame, Olle Bergström, David Erlinge, Chris P Gale, Javier López-Pais, Tomas Jernberg, Pelle Johansson, Annica Ravn-Fisher, Harmony R. Reynolds, Jithendra B. Somaratne, Per Tornvall, Bertil Lindahl. Randomized evaluation of beta blocker and ACE-inhibitor/angiotensin receptor blocker treatment in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA-BAT): Rationale and design. American Heart Journal Volume 231, January 2021, Pages 96-104.

  15. Sikharulidze I, Chelidze K, Mamatsashvili I. Cardiovascular Event Assessment in Patients with Nonobstructive Coronary Artery Disease Undergoing Dua Antiplatelet Therapy. Georgian Medical News. Dec. 2020.

  16. Thygesen K,  Alpert JS, Jaffee AS, et al. Fourth universal definition of myocardial infarction (2018). J Am Coll Cardiol 2018;72:2231-64.

  17. Agewall S, Beltrame JF, Reynolds HR, et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J 2017;38:143-53.

  18. Tamis-Holland JE, Jneid H, Reynolds HR, et al. Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: a scientific statement from the American Heart Association. Circulation 2019;139: e891-e908.

  19. Christina Ekenbäck, Per Tornvall, Stefan Agewall. MINOCA from A to Z. American College of Cardiology. Jan 06, 2022. https://www.acc.org/latest-in-cardiology/articles/2022/01/05/17/41/minoca-from-a-to-z

  20. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 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. Circulation 2014; 129:S49.

  21. Subherwal S, Bach RG, Chen AY, Gage BF, Rao SV, Newby LK, Wang TY, Gibler WB, Ohman EM, Roe MT, Pollack CV Jr.,Peterson ED, Alexander KP. Baseline risk of major bleeding in non‐ST‐segment‐elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress Adverse outcomes with Early Implementation of the ACC/AHA Guidelines) Bleeding Score. Circulation. 2009; 119:1873-1882.

  22. Niccoli G, Scalone G, Crea F. Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management. Eur Heart J. 2015;36:475---81.

  23. Agewall S, Beltrame JF, Reynolds HR, et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J. 2017;38:143---53.

  24. Pasupathy S, Air T, Dreyer RP, et al. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation. 2015;131:861---70.

  25. Safdar B, Spatz ES, Dreyer RP, et al. Presentation, clinical profile, and prognosis of young patients with myocardial infarction with nonobstructive coronary arteries (MINOCA): results from the VIRGO study. J Am Heart Assoc. 2018;7.

  26. Paolisso P, Bergamaschi L, Saturi G, D’Angelo EC, Magnani I, Toniolo S, et al. Secondary prevention medical therapy and outcomes in patients with myocardial infarction with non-obstructive coronary artery disease. Front Pharmacol. (2019) 10:1606. doi: 10.3389/fphar.2019.01606.

  27. Ciliberti G, Verdoia M, Merlo M, Zilio F, Vatrano M, Bianco F, et al. Pharmacological therapy for the prevention of cardiovascular events in patients with myocardial infarction with non-obstructed coronary arteries (MINOCA): insights from a multicentre national registry. Int J Cardiol. (2021)327:9–14. doi: 10.1016/j.ijcard.2020.11.040.

  28. Abdu FA, Liu L, Mohammed AQ, Xu B, Yin G, Xu S, et al. Effect of secondary prevention medication on the prognosis in patients with myocardial infarction with nonobstructive coronary artery disease. J Cardiovasc Pharmacol. (2020) 76:678–83. doi: 10.1097/FJC.0000000000000918.

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