1 Institute of Cardiovascular Diseases, Timisoara, Romania
2 „Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
Editorial comment to
- Anghel et al., “Arrhythmic complications in women with STEMI”
- Ceamburu et al., “Gender equality applies (partially) to ST-segment elevation myocardial infarction too
The present article is based, partly on current data from the Romanian STEMI registry, an experience that is beginning to gain increased contour, partly on original papers published in this current number by colleagues working in coronary care units and invasi-ve cardiology laboratories, papers that are taking into account a subject considered „taboo” until recently – the gender related post-STEMI patient evolution, but also on the editorial „The year in cardiology 2018: acu-te coronary syndromes”, published by Petr Widimsky, Filippo Crea, Ronald K. Binder and Thomas F. Luscher in this January number of European Heart Journal1.
Current statistics (2018) from the Romanian STEMI registry are counting over 12.000 primary PCI or post-thrombolysis invasive procedures, a considerable number that is allowing interesting conclusions and considerations for the European cardiology commu-nity. Beyond a great number of problems concerning management algorithms of acute coronary syndromes, statistics are demonstrating a real progress. In my opi-nion, the latest STEMI diagnostic and treatment guide-line is not that opened in motivating a medical system still seeking optimal logistic and organizing standards, due to the exclusion of the classical „time to balloon” and the introduction of the „time from first medical contact”, a time that may also account a significant delay of time and that is presented as a somehow „ne-gative” patient feature and not a responsibility of the UPU – SMURD – catheterization laboratory system2. Regardless of that fact, the current guideline is presenting the more coherent proposal of the pharma-co-invasive attitude, that is half – dose thrombolysis facilitated angioplasty and complete antithrombotic pre-PCI treatment, an attitude that may be suited not only for patients older than 70 years (we salute the entrance of some Romanian cardiology centers in the European trial STREAM-2). Moreover, one essential fact underlined by the current guideline is the reinfor-cement of the use of thrombolysis, as soon as possible after the onset of symptoms, when the patient cannot reach a 24/24, 7/7 PCI capable center during the first 90 minutes delay of time. Confusions related to this timing started with the 2017 STEMI guideline, with the exclusion of the time from first ischemia related symptoms. Beyond this, another questionable pro-posal of the above mentioned guideline is the useful-ness of PCI after 24 and up to 48 hours after onset of symptoms, including inn asymptomatic patients after the first 12 hours. This new class II indication should not lead to an increased delay of time regarding the revascularization procedure. New data emerged over the last year of global and also European experience need to be highlighted. Although some may seem the-oretical, they are based, without doubt, on evaluati-on and treatment principles that need to be taken in consideration, like adaptive immunity alterations that may trigger inflammation of atherosclerotic plaque, as well as prevalence of erosion in the atheroma poor in aggressive lipids3. This process is most commonly encountered in non ST elevation (NSTEMI) acute coronary syndromes mostly in women, a process that is being four times more frequent than the classical dissection, hemorrhage and plaque thrombosis, well defined by P. Libby and G. Pasterkamp in an already famous European Heart Journal article – „Requiem for the vulnerable plaque”4. This process is the result of almost 3 decades of statins and aspirin use by a great amount of population, both in primary as well as in secondary cardiovascular prevention. The new (the fourth) acute myocardial infarction defi nition is clearly underlying these complex mechanisms in acute coro-nary syndromes and it is also emerging as a result of the year 2018 in cardiology. The evidence of changes in early mortality after STEMI, starting with the years 1950 when coronary care units emerged (45%) to approximately 11-12% in the primary PCI, reperfusion and antithrombotic attitude era, recently underlined by the SWEDEHEART Registry shouldn’t be seen out of the picture in which, the same registry demonstra-ted in the late years a total 4 years mortality of 40%5!
New observations related to myocardial remode-ling and recent studies that analyzed its positive influ-ence (some using osteocrin and some, on-going using ARNI) seem to have promising results, but further evidences are needed. Great effort was put in order to achieve early acute myocardial infarction diagnosis, but the use of new evaluating procedures of high sen-sitive troponins and biomarkers like cysteine-rich an-giogenic inducer 61 Cyr61 or CCN1 have not fulfilled safety reasons yet6.
The new STEMI entity, MINOCA- myocardial in-farction with non-obstructive coronary artery disea-se lead to new clinical and decisional situations, but also to testing some classical provocative agents like acetylcholine and ergonovine administered soon after coronary angiography in order to certify active ische-mia7.
Regarding ST elevation segment acute coronary syndromes in women, some well-known facts are established related to prothrombogenic versus fibri-nolytic factors: decreased plasminogen and increased antithrombogenic factors like Protein C, antithrombin and tissue factor pathway inhibitor, especially in older women. Beyond these classical findings, recent data demonstrated a clear advantage related to hemorrha-gic risk in women when radial approach is preferred. However, pre-procedural maximum statin dose admi-nistration has not proved the same benefi t as in men8. Another finding is that, Takotsubo syndrome, a clinical entity more and more often found in general statistics as an apparently benign form of STEMI, was more frequently encountered in women and, starting with last year, there is a clear etiopathogenic classification of that syndrome9.
The experience of our colleagues from Iasi and re-spectively Cluj-Napoca/Targu Mures regarding gender related differences in acute coronary syndromes evo-lution have demonstrated, in a similar manner with other current foreign studies, a more severe evolu-tion in women following primary PCI in STEMI, both in what concerns the frequency of complications as well as the increased of in-hospital mortality. An ex-planation may be represented by the higher risk sco-re and multiple comorbidities of women analyzed in compare to men, a situation commonly encountered in clinical studies („GENDER EQUALITY APPLIES (PARTIALLY) TO ST-SEGMENT ELEVATION MYO-CARDIAL INFARCTION TOO” – Alexandru Ceam-bur, Razvan Constantin Serban, Ioana Sus, Eva Katalin Lakatos, Zoltan Demjen, Paul Ciprian Fisca, Laszlo Hadadi, Cristina Somkereki, Alina Scridon). On the other hand, arrhythmogenic risk, especially in anterior localization STEMI was greater, both for ventricular fi-brillation as well as for atrial fibrillation, thus leading to an increased relative mortality and early post myocar-dial infarction complications („ARRHYTHMIC COM-PLICATIONS IN WOMEN WITH STEMI”- L. Anghel, Cristina Prisacariu, Amin Bazyani, Liviu Macovei). Results are demonstrating that, in older women, the frailty and vulnerability may lead to an increased short and long term mortality after an invasive revascula-rized STEMI. Also, a recent Scandinavian study also found gender differences and significant delay related to first medical contact and optimal reperfusion time, much more frequent in women patients in compare to male ones, due to confusion in diagnostic10.
Another controversy is related to primary PCI in elderly patients, especially patients older than 80 years. This is also a sensitive issue in Romanian hos-pitals, not only for economical and logistic reasons. A recent American Heart Association paper published an evaluation of over 470.000 elderly patients, during 16 years of follow-up, patients that benefit from pri-mary PCI in STEMI. The decrease for the risk of death of any cause was 53% for patients with age between 75 and 79 years, 49% for patients with age between 80 and 84 years and 42% for patients older than 85. This data should determine the use of an unequivocal attitude regarding the effi cacy and morality of the pre-ferred revascularization method. Beyond new data in the field, another debated subject is represented by the optimal antithrombotic treatment. When taking into account older women, thrombotic risk has an unacceptable increase after prolonged antiplatelet aggressive therapy (including anticoagulants) – prasugrel, ticagrelor, thus underlying the need for a closer monitoring of this category of patients and the consideration of more „softer” mole-cules like clopidogrel, especially after the first month of DAPT – double antiplatelet therapy (TROPICAL ACS, CHANGE DAPT, TOPIC etc.).11 An interesting issue is represented by non-valvular atrial fi brillation patients with the need for PCI, including STEMI, with the option for double antiplatelet antithrombotic the-rapy (direct oral anticoagulant – DOAC plus aspirin or Clopidogrel/Ticagrelor) certified by at least three clinical studies – PIONEER AF-PCI, RE-DUAL and AU-GUSTUS, versus triple antithrombotic therapy (anti-coagulant plus double antiplatelet treatment), all stu-dies with results that demonstrated lower hemorrha-gic risks and antithrombotic benefits for the DOAC plus aspirin or Clopidogrel/Ticagrelor combination. However, recent data from the VALIDATE-SWEDE-HEART trial and MATRIX trial did not confirm the use of bivalirudine versus unfractionated heparin in the pre-procedural setting, in order to decrease he-morrhagic risk12.
Promising study results with decreased mortality rate after two years of follow-up were found using a new generation of hypolipemiant medication – PCSK-9 inhibitors – ODYSSEY OUTCOMES using alirocumab and FOURIER using evolocumab13. However, beyond the fact that further studies are needed, in the setting of a restrictive economic Romanian environment, the increased price of that medication represents an im-portant issue.
Another important controversy is represented by multivascular approach, beyond culprit coronary lesi-on, in acute coronary syndromes patients, an approach that may be considered during index hospitalization or in a staged procedure. For patients with STEMI and cardiogenic shock, the CULPRIT-SHOCK trial de-monstrated, despite previous results, lower early and medium-term mortality rates when using culprit lesion approach only in compare to multivascular approach during the same procedure14.
Another issue of controversy was verified by the VERDICT trial, with results that demonstrated the fact that, in the case of a NSTEMI acute coronary syndrome with a GRACE score inferior to 140, there is no sufficient need for early revascularization procedure (mean time 4,7 hours) versus delayed revascula-rization approach (61,6 hours)15.
Regarding percutaneous revascularization of left main lesions in acute coronary syndromes, the results of DELTA-2 registry brought optimism of investiga-tors and medical specialized community. Gender diffe-rences in STEMI/NTEMI patients were evaluated by a Canadian registry – SCAD Cohort study that also de-monstrated the prevalence of spontaneous coronary dissection in average age with overt stress factors wo-men patients16.
An unsolved issue, associated with high mortality rate is represented by the approach of patients with unstable hemodynamic status following cardiac re-suscitation after ventricular fibrillation in STEMI, with mortality rates up to 60% during the first year and irreversible cerebral damage, despite the use of ven-tricular mechanical devices like IMPELLA or ECMO. Unfortunately, these devices are rarely used in our country, with an even higher mortality rate in these situations. The door-to-balloon-time is another defi – cient indicator in many areas, including our country, due to logistical and organization issues that are well known in the few PCI capable centers across Romania. Concerning novel anti-inflammatory therapies (CAN-TOS) and the use of stem cells in order to replace ne-crotic myocardial tissue, a reasonable amount of time must elapse before routine use.
Despite progress but also deficiencies that were hi-ghlighted in this article, my opinion is that we are wit-nessing an increased trend regarding the improvement in morbidity- mortality rates after STEMI/NSTEMI acute coronary syndromes patients, but, even more important, of primary prevention measures implemen-ted in order to avoid these severe pathology with irreversible consequences over the quality and duration of patients life.
Conflict of interest: none declared.
1. Petr Widimsky, Filippo Crea, Ronald K. Binder, and Thomas F. Luscher, The year in cardiology 2018: acute coronary syndromes. European Heart Journal (2019) 40, 271–283.
2. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P. 2017 ESC Guidelines for the manage-ment of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myo-cardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119– 177.
3. Angelini G, Flego D, Vinci R, Pedicino D, Trotta F, Ruggio A, Piemon-tese GP, Galante D, Ponzo M, Biasucci LM, Liuzzo G, Crea F. Ma
trix metalloproteinase-9 might affect adaptive immunity in non-ST segment elevation acute coronary syndromes by increasing CD31 cleavage on CD4þ T-cells. Eur Heart J 2018;39: 1089–1097.
4. P Libby, G Pasterkamp – Requiem for the ’vulnerable plaque’, Eur Heart Journal, 2015; 36: 2984–2987.
5. Edfors R, Sahlen AS, Szummer KS, Renlund HR, Evans ME, Carrero JJ, Spaak JS, Lagerqvist BL, James SJ, Varenhorst CV, Jernberg TJ. Outcomes in patients treated with ticagrelor versus clopidogrel af-ter acute myocardial infarction in relation to renal function: 1-year SWEDEHEART registry data. Eur Heart J 2017; 38(Suppl_1):ehx493. doi:10.1093/eurheartj/ehx493.6011.
6. Miyazaki T, Otani K, Chiba A, Nishimura H, Tokudome T, Takano-Watanabe H, Matsuo A, Ishikawa H, Shimamoto K, Fukui H, Kanai Y, Yasoda A, Ogata S, Nishimura K, Minamino N, Mochizuki N. A new secretory peptide of natriuretic peptide family, osteocrin, sup-presses the progression of congestive heart failure after myocardial infarction. Circ Res 2018;122:742–751.
7. Montone RA, Niccoli G, Fracassi F, Russo M, Gurgoglione F, Camma G, Lanza GA, Crea F. Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests. Eur Heart J 2018;39:91–98.
8. Peters SAE, Colantonio LD, Zhao H, Bittner V, Dai Y, Farkouh ME, Monda KL, Safford MM, Muntner P, Woodward M. Sex differences in high-intensity statin use following myocardial infarction in the United States. J Am Coll Cardiol 2018; 71:1729–1737.
9. Ghadri JR, Wittstein IS, Prasad A, Sharkey S, Dote K, Akashi YJ, Cammann VL,Crea F, Galiuto L, Desmet W, Yoshida T, Manfredini R, Eitel I, Kosuge M, Nef HM, Deshmukh A, Lerman A, Bossone E, Citro R, Ueyama T, Corrado D, Kurisu S,Ruschitzka F, Winchester D, Lyon AR, Omerovic E, Bax JJ, Meimoun P, Tarantini G, Rihal C, Y-Hassan S, Migliore F, Horowitz JD, Shimokawa H, Lüscher TF, Templin C.International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology. Eur Heart J. 2018 Jun 7;39(22):2032-2046.
10. Ängerud KH, Sederholm Lawesson S, Isaksson RM, Thylén I, Swahn E. Differences in symptoms, first medical contact and pre-hos-pital delay times between patients with ST- and non-ST-elevation myocardial infarction. Eur Heart J Acute CardiovascCare. 2019 Apr;8(3):201-207.
11. Sibbing D, Gross L, Trenk D, Jacobshagen C, Geisler T, Hadamitzky M, MerkelyB, Kiss RG, Komócsi A, Parma R, Felix SB, Neumann FJ, Hausleiter J, Baylacher M, Koltowski L, Mehilli J, Huber K, Huc-zek Z, Aradi D, Massberg S; TROPICAL-ACS Investigators. Age and outcomes following guided de-escalation of antiplatelet treatment in acute coronary syndrome patients undergoing percutaneous coronary intervention: results from the randomized TROPICAL-ACS trial. Eur Heart J. 2018 Aug 1;39(29):2749-2758.
12. Gargiulo G, Ariotti S, Vranckx P, Leonardi S, Frigoli E, Ciociano N, Tumscitz C, Tomassini F, Calabro P, Garducci S, Crimi G, Ando G, Ferrario M, Limbruno U, Cortese B, Sganzerla P, Lupi A, Russo F, Garbo R, Ausiello A, Zavalloni D, Sardella G, Esposito G, Santarelli A, Tresoldi S, Nazzaro MS, Zingarelli A, Petronio AS, Windecker S, da Costa BR, Valgimigli M. Impact of sex on comparative outcomes of radial versus femoral access in patients with acute coronary syn-dromes undergoing invasive management: data from the randomized MATRIX-access trial. JACC Cardiovasc Interv 2018;11:36–50.
13. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM; ODYS-SEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–2107.
14. Thiele H, Akin I, Sandri M, de Waha-Thiele S, Meyer-Saraei R, Fuer-nau G, Eitel I, Nordbeck P, Geisler T, Landmesser U, Skurk C, Fach A, Jobs A, Lapp H, Piek JJ, Noc M, Goslar T, Felix SB, Maier LS, St-epinska J, Oldroyd K, Serpytis P, Montalescot G, Barthelemy O, Hu-ber K, Windecker S, Hunziker L, Savonitto S, Torremante P, Vrints C, Schneider S, Zeymer U, Desch S; CULPRITSHOCK Investigators. One-year outcomes after PCI strategies in cardiogenic shock. N Engl J Med 2018;379:1699–1710.
15. Kofoed KF, Kelbaek H, Hansen PR, Torp-Pedersen C, Hofsten D, Klovgaard L, Holmvang L, Helqvist S, Jorgensen E, Galatius S, Ped-ersen F, Bang LE, Saunamaki K, Clemmensen P, Linde JJ, Heitmann M, Nielsen OW, Raymond IE, Kristiansen OP, Svendsen IH, Bech J, Vall-Lamora MHD, Kragelund C, FritzHansen T, Hove JD, Jorgensen T, Fornitz GG, Steffensen R, Jurlander B, Abdulla J, Lyngbaek S, El-ming H, Therkelsen SK, Abildgaard U, Jensen JS, Gislason G, Kober LV, Engstrom T. Early versus standard care invasive examination and treatment of patients with non-ST-segment elevation acute coro-nary syndrome: the VERDICT (Very EaRly vs Deferred Invasive eval-uation using Computerized Tomography)—randomized controlled trial. Circulation 2018;138:2741–2750.
16. Saw J, Starovoytov A, Humphries K, Sheth T, So D, Minhas K, Brass N, Lavoie A,Bishop H, Lavi S, Pearce C, Renner S, Madan M, Welsh RC, Lutchmedial S,Vijayaraghavan R, Aymong E, Har B, Ibra-him R, Gornik HL, Ganesh S, Buller C, Matteau A, Martucci G, Ko D, Mancini GBJ. Canadian spontaneous coronary artery dissection cohort study: in-hospital and 30-day outcomes. Eur Heart J. 2019 Apr14;40(15):1188-1197.