Keywords

Acute coronary syndrome, dual antiplatelet agent therapy, emergency percutaneous coronary intervention, ST elevation myocardial infarction, ticagrelor, type 2 diabetes mellitus

The standard treatment for acute coronary syndrome (ACS) involves therapy with antiplatelet, anticoagulant and thrombolytic agents, and the performance of percutaneous coronary intervention (PCI). Platelet function disorders leading to an accelerated process of atherosclerosis and increased risk for atherothrombotic complications occurs in type 2 diabetes mellitus (T2DM).

Previous studies suggest a worse outcome for diabetic patients after acute coronary events.1 Recently, a high variability of response to clopidogrel measured by platelet function tests has been reported among patients with PCI and hyporesponsiveness to clopidogrel has been considered to influence cardiac outcome in these patients.2 Impaired response to antiplatelet therapy in diabetic patients has been reported in small patient collectives.3

Since, the advent of reperfusion therapy for acute ST elevation myocardial infarction (STEMI) the “open artery hypothesis” proposed that the benefit is achieved from early reperfusion of occluded coronary artery, which limits the size of infarction, reduces the degree of left ventricular dysfunction and improves survival.4 PCI is one of the two coronary revascularization techniques currently used in the treatment of ischemic heart disease (IHD), the other being coronary artery bypass grafting (CABG).5 PCI involves nonsurgical widening of the coronary artery, using a balloon catheter to dilate the artery from within and deploying usually a metallic stent in the artery after dilatation.

Clopidogrel a second-generation irreversible inhibitor of antiplatelet is considered the standard care for preventing coronary thrombus in patients diagnosed with STEMI who will undergo PCI but due to its drawbacks like long onset of action and time to maximum inhibition of platelet activation (IPA) especially treating patients with risk factors like T2DM thereby leading to an increased risk of thrombotic events, a new drug “ticagrelor which not only has short onset of action and time to maximum IPA but also has a good response in these type of patients undergoing emergency PCI has been recently suggested by US Food and Drugs Administration (FDA) as well as in the recently published treatment guidelines”. In this case, the patient was planned for emergency PCI using this useful drug “ticagrelor” as one of the main drug for dual antiplatelet therapy (DAPT). Our case report, therefore, emphasizes on the characteristics and the management of elderly patients with diabetes with high cardiovascular risk undergoing emergency PCI using ticagrelor instead of the standard drug clopidogrel widely used today.

CASE PRESENTATIONA 73-year-old male with a history of T2DM, hypertension and previous history of cerebral infarction and pulmonary tuberculosis, presented to our Emergency Department of Cardiology, Jingzhou Central Hospital, on 5th July 2014 with a chief complaint of substernal chest pain since 5 hours, which was continuous and nonradiating. His vitals were: pulse rate - 76 beats/min, blood pressure (BP) - 110/70 mmHg, respiratory rate - 20/min and temperature - 36.5°C. A 12-lead emergency electrocardiography (ECG) was done immediately which showed sinus rhythm with ST-segment elevation in leads II, III and AVF and T-wave inversion (Fig. 1). The blood reports for cardiac enzymes revealed raised troponin I (0.53 µg/L), which indicated confirmatory diagnosis of acute inferior wall myocardial infarction (MI) with ST elevation. He was immediately treated with loading doses of aspirin 300 mg and ticagrelor 180 mgas a dual antiplatelet therapy after taking strict consent from the patient and was further planned for emergency PCI. He was also given rosuvastatin 10 mg stat and nitroglycerine 5 mg intravenous through pump at 3 mL/hour. He was planned for emergency PCI and emergently rushed to the cardiac catheterization lab. At the time of procedure, he had ongoing chest pain and showed evidence of persistent ST elevation on the ECG. After routine disinfection, the right radial artery was punctured by Seldinger method. Thereafter, 2,000 Uof heparin was injected to the patient. The coronary angiography revealed normal left main coronary artery; whereas, there was 90-95% stenosis in the proximal part of left anterior descending (LAD) artery (Fig. 2) and complete occlusion of middle part of left circumflex (LCx) artery, being the culprit one (Fig. 3). The LCx also had a second site of stenosis near the proximal part (Fig. 3). We then introduced a 6F XB-3.0 guiding catheter till the left crown and an additional 6,000 Uof heparin was injected. Tirofiban 10 mL was directly injected on the coronary artery keeping in mind the amount of thrombus it contained. After which, run through NS distal guidewire was introduced into the LCx and 2.0 × 20 mm balloon inflation was done with 16 atm on stenosed sites of the culprit part of the artery (Fig. 4). Then implantation of BUMA 3.5 × 20 mm (Fig. 5) and 3.0 × 25 mm (Fig. 6) bracket 2 stent were deployed at both the sites, respectively. At the end of the procedure TIMI flow 3 was established (Fig. 7).

The total amount of contrast agent (Omnipaque) used throughout the procedure was about 150 mL. Dopamine was also infused throughout the procedure via infusion pump at a rate of 5 mL/hour because the patient had consistently decreasing BP. The total time taken for the PCI operation (door to balloon) was 60 minutes. After the PCI, the patient was kept in the cardiac care unit (CCU) with continuous ECG monitoring for few days and then transferred to the cardiology ward. His post-PCI 12-lead ECG revealed that ST-segment elevation had decreased to a greater extent on all three leads II, III and AVF with the formation of Q-wave (Fig. 8). During his stay post-PCI, he was kept on aspirin 100 mg o.d., ticagrelor 90 mg b.i.d., isosorbide dinitrate 40 mg o.d., rosuvastatin 10 mg o.d., perindopril 4 mg o.d. and a low-dose of metoprolol 6.25 mg o.d. After normalizing his BP, he was sent for Doppler echocardiography to rule out any form of left ventricular aneurysm and evaluate the function of his heart through ejection fraction (EF), which luckily came out to be normal. On the 7th post-PCI day, rales were heard on bases of both lungs during auscultation without any specific symptoms, hence computed tomography (CT) scan was ordered.

The CT scan report revealed ongoing infection on bilateral lung fields. So, the patient was started with cefaperazone 2 g b.i.d. to treat the ongoing infection. The patient was finally discharged on the 12th post-PCI day and advised to continue aspirin, rosuvastatin for rest of his life, isosorbide dinitrate for 1 month, perindopril and metoprolol according to his BP fluctuation. Ticagrelor was asked to be continued for 1 year in a dose of 90 mg b.i.d. The patient was further counseled about his diet control and was strictly suggested to change his lifestyle.

FOLLOW-UPThe patient was strictly asked to come to follow-up for another PCI of LAD after 1 month. He presented at the outpatient department (OPD) at the stipulated period, but he refused to undergo second PCI due to some personal problems, financial being one of them. He was doing pretty well without any ongoing symptoms at the time. An ECG was done, which did not reveal any significant changes except the Q waves.

Cardiac biomarkers were also repeated, which were near normal range. He was therefore, advised to continue the same medications and was called for next follow-up after 3 months. At the next follow-up, 4th month post-PCI, the patient was doing well and was advised to continue same medications except for perindopril and metoprolol whose doses were changed according to his BP.

DISCUSSIONCoronary heart disease (CHD) is the first cause of morbidity and mortality in diabetic patients. Its incidence in elderly patient increases with the increase of their life expectancy. On the other hand, the quality-of-life of the diabetics after PCI is better to conventional therapy. Elderly diabetic patients are very high cardiovascular risk, characterized by the severity of coronary artery disease (CAD). They are treated less aggressively than nondiabetics in spite of the fact that diabetic’s quality-of-life improves better with angioplasty in comparison with the conventional treatment. Ticagrelor is the first antiplatelet agent that achieves a significant reduction in cardiovascular mortality in STEMI patients in comparison to clopidogrel and the most important part of it is that it carries out its task without an increase in major bleeding. A similar magnitude of reduction in ischemic events has also been seen with another agent i.e., prasugrel when compared with clopidogrel but it differs from ticagrelor in the fact that the benefit of ticagrelor continues to a greater extent over the course of the therapy. Thus advantages of ticagrelor over clopidogrel and prasugrel is more regardless of whether patients receive invasive or medical management or whether PCI. So, our team found ticagrelor suitable and a boon for this high-risk patient in the management of STEMI.

Treatment of patients with ACS routinely involves PCI and use of intracoronary stents. Stent thrombosis is a life-threatening complication which may occur acutely (i.e., in the first 24 hours), subacutely (i.e., from 24 hours to 30 days) or late after stent placement.6 It is more frequent when platelet inhibition by aspirin and clopidogrel is inadequate.7 As we have already discussed earlier, clopidogrel, in particular, produces a moderate and variable inhibition of P2Y12, whereas ticagrelor provides more potent and consistent platelet inhibition with faster onset and offset of action than clopidogrel. Stent thrombosis has always been a challenging task after PCI for cardiologists today. This fast acting novel reversible antiplatelet agent “ticagrelor” lowers the rate of stent thrombosis in patients who receive stents when compared to patients taking clopidogrel,8 which has also been proved in our case by the fact that the patient did not develop stent thrombosis.

The superior clinical efficacy demonstrated by the oral, reversible, P2Y12 receptor inhibitor antiplatelet agent ticagrelor compared with the standard antiplatelet agent clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial may be due in large part to the former’s greater platelet inhibition exhibited both during the maintenance phase and the first hours of treatment. In PLATO trial, ticagrelor reduced the primary endpoint of cardiovascular death, MI and stroke when compared with clopidogrel.9 In another substudy, PLATO PLATELET, patients were randomized to receive either clopidogrel (300-600 mg loading dose [LD], 75 mg/day) or ticagrelor (180 mg LD, 90 mg twice-daily) and the effects of maintenance therapy were studied in ACS patients pre- and 2-4 hours post-dose after at least 28 days. It was concluded that, ticagrelor achieved greater antiplatelet effect than clopidogrel in patients with ACS, both in the first hours of treatment and during maintenance therapy.9 Therefore, we can say ticagrelor demonstrates a more rapid onset and greater platelet inhibitory effect than clopidogrel in ACS patients both during maintenance therapy and in the first hours of treatment. It is also superior to clopidogrel in reducing ischemic events, without any increase in major bleeding.

According to the PLATO trial, dyspnea was the more common side effect during the initial days of treatment in the ticagrelor group compared with the clopidogrel group.10 Thus keeping in mind these side effects, special precautions and care were taken during the procedure as well as in dosing ticagrelor throughout the treatment tenure but we did not come across any kind of adverse effects in this elderly patient except for the lung infection in the patient who was already on prophylactic antibiotic, which was diagnosed promptly and managed accordingly.

CONCLUSIONIn conclusion, patient with history of T2DM and hypertension as huge risk factors presenting with STEMI within 12 hours of ongoing symptom, can be treated with emergency PCI along with antiplatelet, anticoagulant and thrombolytic agents. DAPT should be started as soon as it is diagnosed with ticagrelor being one of them which is not only the first reversible, nonthienopyridine, direct P2Y12 blocker antiplatelet agent having a short onset of action and time to maximum IPA but also has a good response in these types of elderly patients with T2DM undergoing emergency PCI. Though ticagrelor is a very propitious novel antiplatelet drug with impressive efficacy and reasonable safety, special care should always be taken to deal with any kind of side effects and rule out any symptoms we come across be it during the admission, treatment tenure, after discharge and even during follow-up because any symptom in the patient may mimic the side effects of ticagrelor stated above.

REFERENCES

1. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M.Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229-34.
2. Geisler T, Langer H, Wydymus M, Gohring K, Zurn C, Bigalke B, et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J. 2006;27(20):2420-5.
3. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Sabate M, Jimenez-Quevedo P, et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes. 2005;54(8):2430-5.
4. Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival: should the paradigm be expanded? Circulation. 1989;79(2):441-4.
5. Kalyanasundaram A. Comparison of revascularization procedures in coronary artery disease. Medscape. Apr 2012.
6. Ong AT, Hoye A, Aoki J, van Mieghem CA, Rodriguez Granillo GA, Sonnenschein K, et al. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation. J Am Coll Cardiol. 2005;45(6):947-53.
7. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16):1821-30.
8. Steg PG, Harrington RA, Emanuelsson H, Katus HA, Mahaffey KW, Meier B, et al. Stent thrombosis with ticagrelor versus clopidogrel in patients with acute coronary syndromes: an analysis from the prospective randomized PLATO trial. Circulation. 2013;128(10):1055-65.
9. Storey RF, Angiolillo DJ, Patil SB, Desai B, Ecob R, Husted S, et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient outcomes) PLATELET substudy. J Am Coll Cardiol. 2010;56(18):1456-62.
10. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-57.