Magnesium as a predictor of acute stent thrombosis in patients with ST-segment elevation myocardial infarction who underwent primary angioplasty

Abstract

Background 

Although magnesium (Mg) has been proposed as a useful biomarker for predicting atherothrombosis, the association between Mg and acute stent thrombosis (ST) after primary percutaneous coronary intervention (p-PCI) for ST-segment elevation myocardial infarction (STEMI) has not yet been defined.

Objectives 

We aimed to examine whether admission Mg levels predicted the development of acute ST after p-PCI in STEMI patients.

Methods and results 

A total of 2633 patients with STEMI who underwent p-PCI were retrospectively analyzed. Acute ST was defined as thrombosis that occurred in the first (0–1) days following primary coronary stenting, and patients who had undergone p-PCI were divided into two groups: ST group and no-ST group. The cut-off value for Mg obtained by the receiver-operating characteristic curve analysis was less than 1.91 mg/dl for the prediction of acute ST (area under the curve was 0.761; 95% confidence interval, 0.706–0.816; P<0.001; sensitivity, 70%; specificity, 69%). Serum Mg levels were significantly lower in the ST group compared with the no-ST group (median 1.80 mg/dl, interquartile range 1.70–2.00 mg/l vs. median 2.10 mg/dl, interquartile range 1.90–2.20 mg/dl, P<0.001). After multivariable adjustment for clinical, laboratory, and angiographic variables, Mg remained a strong independent predictor for acute ST (odds ratio 5.802, 95% confidence interval, 3.069–10.967; P<0.001).

Conclusion 

Serum Mg level is associated independently with the risk of acute ST in patients with STEMI who undergo p-PCI.

Introduction

Coronary artery stents are used in the majority of patients who undergo a primary percutaneous coronary intervention (p-PCI) as they significantly reduce the need for repeat target vessel revascularization compared with balloon angioplasty ¹. One of the main concerns remaining with stenting of the patients with acute myocardial infarction (AMI) is the development of stent thrombosis (ST). ST is an uncommon but serious complication that almost always presents as death or a large nonfatal myocardial infarction, usually with ST elevation ². It has been reported that there is a persistent and increased risk of early ST in patients with moderate-risk to high-risk acute coronary syndromes, irrespective of the implanted stent type ³.

Magnesium (Mg) is the second most abundant intracellular cation, and it is extremely important for more than 300 enzymatic reactions that are involved in various metabolic processes in the human body; still, it is a parameter that is overlooked by the clinicians ⁴. Observational and experimental studies showed that Mg could exert useful effects on the cardiovascular system by enhancing endothelium-dependent vasodilation, improving lipid metabolism, reducing inflammation, and inhibiting platelet function ⁵. It was shown that Mg could suppress platelet activation by multiple pathways ^6,7. Transient hypomagnesemia is common during the first 2–5 days after AMI, and may be associated with an increased rate of arrhythmias, reinfarction, and death ⁸. Although there is an association between serum Mg levels and total cardiovascular disease events ⁹, the underlying pathophysiology remains unclear.

To the best of our knowledge, no studies to date have investigated the relationship between serum Mg level and development of acute ST in the setting of ST-segment elevation myocardial infarction (STEMI). The aim of the present study was to assess whether serum Mg concentration was related to an increased risk of acute ST after p-PCI in patients with STEMI.

Methods

Patient population

After obtaining approval from the local ethics committee, we retrospectively assessed 2633 consecutive patients with STEMI who were admitted to the Emergency Department of our hospital and underwent the p-PCI procedure in our catheter laboratory. All patients provided written informed consent. Patients were enrolled in the study if they fulfilled the following criteria: (i) if they presented within 12 h from the onset of symptoms (typical chest pain lasting for>30 min), (ii) if there was ST-segment elevation of at least 2 mm in at least two contiguous ECG leads, or new onset of complete left bundle-branch block, and (iii) patients with p-PCI (angioplasty and/or stent deployment). Patients with active infection, autoimmune diseases, hematological proliferative diseases, or neoplasia were excluded. A total of 319 patients were excluded because of absence of any indications for PCI (n=95), coronary bypass surgery (n=84), missing or unavailable Mg value (n=99), dialysis history (n=8), and because of procedural reasons (n=41). Procedural exclusion criteria were a residual stenosis more than 10%, dissection or abrupt closure, need for three or more stents, postprocedurally discovered dissection, undersizing, postprocedural thrombolysis in myocardial infarction (TIMI) flow less than 3, bifurcation stenting, stenosis greater than 50% proximal of the culprit lesion left untreated, prior brachytherapy, residual thrombus, or persistent dissection after stent placement. Therefore, the final study population included 2306 patients. All p-PCI procedures were performed in a single high-volume tertiary center (>3000 PCI/year) by expert operators performing more than 75 PCIs per year.

Data sources

Demographic information and cardiovascular history including cardiovascular risk factors such as smoking, hypertension, and diabetes mellitus (DM) were obtained from the medical records. Angina-to-reperfusion time was also obtained during hospital stay. ECG was performed, and complete blood counts and other serum parameters (potassium, creatinine, glucose, etc.) were determined on admission before catheterization procedures. Antecubital venous blood samples were also obtained on admission for determination of serum Mg values. Serum Mg concentration was determined using a Roche/Hitachi MODULAR analyzer (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) with a xylidyl blue reaction in accordance with the manufacturer’s instructions. The magnesium levels were expressed in milligrams per deciliter (mg/dl).

Coronary angiography, primary angioplasty, and stenting

All patients received chewable acetyl salicylic acid (300 mg) and clopidogrel (600 mg loading dose) before the coronary angiography. Emergency coronary angiography and stenting were performed through the percutaneous femoral approach. After visualizing the left and right coronary arteries, 1 mg of glyceryl trinitrate was selectively injected into the infarct-related artery (IRA) to rule out a possible coronary spasm. Two experienced interventional cardiologists performed the angiographic assessments. Intraobserver and interobserver variabilities for ST analysis were evaluated in a representative subset of 80 patients. The interpretations of two investigators on the presence or absence of ST showed 100% (80 of 80) and 100% (80 of 80) agreement, respectively. Intraobserver variability was assessed by one investigator. Two readings of this investigator were in concordance for the presence or absence of ST in 100% (80 of 80) and 97.5% (78 of 80), respectively. The IRA was graded according to the TIMI classification ¹⁰. Primary coronary stenting was performed only for IRA. Stents were deployed in accordance with the standard techniques. All patients received unfractionated heparin intravenously during the procedure (70 U/kg bolus).We used point-of-care activated clotting time to monitor facilitated heparin dose titration during PCI: activated clotting time longer than 250–300 s if no glycoprotein IIb/IIIa inhibitor is administered and longer than 200–250 s if a glycoprotein IIb/IIIa inhibitor is administered. Heparin infusion (to maintain the activated partial prothrombin time between 80 and 150 s) was administered during the first 24 h. The use of glycoprotein IIb/IIIa inhibitors was left to the discretion of the operator. After stenting, all patients were prescribed acetyl salicylic acid (100 mg daily) lifelong, and clopidogrel (75 mg daily) was prescribed for at least 1 month. Concomitant medical treatment with β-blockers, angiotensin-converting enzyme inhibitors, and statins was administered according to the guidelines of the American College of Cardiology/American Heart Association ¹¹.

Definition

Acute ST was defined according to the Academic Research Consortium ¹². Primary PCI for definite ST was considered a PCI on angiographic confirmation of a thrombus that originated in the stent, or in the segment 5 mm proximal or distal to the stent, with or without vessel occlusion, which was associated with acute onset of ischemic symptoms at rest or ECG signs of acute ischemia or a typical rise and fall of in cardiac biomarkers within 48 h of angiography, OR pathologic confirmation of ST determined at autopsy, or from tissue obtained following thrombectomy ¹³. Acute ST was defined as thrombosis that occurred in the first (0–1) days following primary coronary stenting. Accordingly, patients with primary PCI were divided into ST and no-ST groups. Time to reperfusion was measured as the time from the onset of symptoms to the coronary reperfusion acquired with balloon inflation. DM was defined as a previous diagnosis, use of antidiabetic medicines, or a fasting venous blood glucose level of at least 126 mg/dl on two occasions in previously untreated patients. Hypertension was defined as previous use of antihypertensive medication, a systolic pressure greater than 140 mmHg, or a diastolic pressure greater than 90 mmHg on at least two separate measurements. The estimated glomerular filtration rate (eGFR) was calculated using the modified modification of diet in renal disease equation ¹⁴: eGFR (ml/min/1.73 m²)=186×(S_Cr)^−1.154×(age)^−0.203(×0.742 in women), where S_Cr defines the serum creatinine concentration in milligrams per deciliter as measured immediately before p-PCI and age is given in years.

Statistical analysis

Statistical analysis was carried out using the SPSS statistical package, version 18.0 (SPSS Inc., Chicago, Illinois, USA) for Windows. All values are expressed as mean±SD or as median and interquartile range. Differences between the means were compared using an unpaired t-test when the variables showed a normal distribution or using the Mann–Whitney U-test when they did not show a normal distribution. Categorical variables were presented as counts and percentages, and compared between the groups using the χ²-test. Multiple logistic regression models were used to analyze the association between plasma Mg level and the occurrence of acute ST, and odds ratio (OR) and 95% confidence interval (CI) were calculated. Receiver-operating characteristic analysis was carried out to determine the cut-off value of Mg for predicting acute ST. Multivariate logistic regression analysis was carried out to identify the independent predictors of acute ST. All variables with a significance value less than 0.1 on univariate analysis (DM, stent length, Mg) were included in the model. A P value less than 0.05 was considered statistically significant.

Results

The study population included 2306 patients with STEMI, mean age 56.74±11.96 years; 1897 (82.2%) were men. Acute ST was observed in 47 (2.04%) patients. Baseline clinical characteristics of the study population are shown in Table 1. Groups with and without ST were similar in terms of cardiovascular risk factors. Serum Mg levels were significantly lower in the ST group compared with the no-ST group (median 1.80 mg/dl, interquartile range 1.70–2.00 mg/l vs. median 2.10 mg/dl, interquartile range 1.90–2.20 mg/dl, P<0.001). Other laboratory findings were similar between the groups. Laboratory data of the study population are summarized in Table 2. In the study population, the cut-off value for Mg obtained by the receiver-operating characteristic curve analysis was less than 1.91 mg/dl for the prediction of acute ST (area under the curve was 0.761; 95% CI, 0.706–0.816; P<0.001; sensitivity 70%; specificity 69%; Fig. 1). The patients’ angiographic and procedural characteristics were similar in two groups. Angiographic and procedural characteristics of the study population are shown in Table 3. Univariate logistic regression analysis indicated that Mg less than 1.91 mg/dl was a highly significant predictor of acute ST (OR 5.217; 95% CI 2.775–9.810; P<0.001). After multivariable adjustment for clinical, laboratory, and angiographic variables, Mg remained a strong independent predictor of acute ST (OR 5.802; 95% CI 3.069–10.967; P<0.001; Table 4).

Table 1: Baseline characteristics of the patients included in the study

Table 2: Laboratory findings of the patients

Fig. 1: Receiver-operating characteristic (ROC) curve analysis of serum magnesium for predicting acute stent thrombosis. AUC, area under the curve; CI, confidence interval.

Table 3: Angiographic and procedural characteristics of the patients

Table 4: Multivariate predictors of acute ST

Discussion

In this study, we showed for the first time that admission Mg level was an independent and significant predictor of acute ST in patients who had p-PCI for STEMI.

The risk factors for development of ST include procedural factors, patient-related, lesion-related, and stent-related factors, and cessation of antiplatelet therapy ¹⁵. The procedural factors associated with an increased risk of acute ST are residual stenosis more than 10%, dissection or abrupt closure, need for three or more stents, postprocedurally discovered dissection, undersizing, postprocedural (TIMI) flow less than 3, bifurcation stenting, stenosis greater than 50% proximal of the culprit lesion left untreated, residual thrombus or persistent dissection after stent placement, previous brachytherapy, no aspirin at the time of the procedure, and malignancy ^3,16–18. Patients with these risk factors were excluded from our study to assess the role of Mg in acute ST with minimal confounding factors.

A number of noncoronary clinical factors such as DM ^17–19, creatinine level on admission ², and baseline white blood cell ²⁰ and platelet ²¹ counts were associated with ST. In our study, none of these variables were found to be independent predictors of acute ST, except baseline Mg level (Table 2).

The role of Mg in the pathogenesis of ST is not clear. It was reported previously that Mg could impede platelet activation by either inhibiting platelet-stimulating factors such as thromboxane A2 or by stimulating synthesis of platelet-inhibitory factors such as prostacyclin (prostaglandin I2) ^6,7. It was shown to stimulate the release of those vasodilating and antiaggregatory substances from the endothelium ²². Low Mg levels were shown to inhibit endothelial proliferation and migration, and upregulate the expression of interleukin (IL)-1, IL-6, vascular cell adhesion molecule, and plasminogen activator inhibitor-1, thereby producing a proinflammatory, prothrombotic, and proatherogenic environment ²³. In addition, Mg is a well-known calcium blocker ²⁴, and calcium plays significant roles both in platelet activation and in the coagulation cascade ²⁵. Magnesium exerts its platelet-inhibitory effect by reducing calcium mobilization in platelets and it may also suppress fibrinogen interaction with platelets by competitive inhibition of calcium at the calcium-binding sites of the glycoprotein IIb/IIIa complex ²⁶. Although our study does not fully clarify the mechanism of the association of Mg with acute ST, the possible explanations include improved vascular tone and endothelial function, reduced platelet aggregation, increased HDL, and improved glucose and calcium homeostasis performed by Mg ^25,27, all of which are suggested to be potential causes of acute ST.

Animal studies showed the association of Mg levels with thrombus formation. Rukshin et al.²⁸ showed in a canine model that Mg produced a significant reduction in acute stent thrombus formation, and this was equivalent in magnitude to that produced by clinically relevant doses of tirofiban and eptifibatide. In our study, the rates of the use of glycoprotein IIb/IIIa inhibitors in ST and no-ST groups were similar. This may be related to exclusion of the patients with procedural characteristics, leading to the use of glycoprotein IIb/IIIa inhibitors, such as residual thrombus. Rukshin et al.²⁹ also showed that intravenous Mg produced a significant inhibition of acute platelet-dependent ST in a swine model. Beneficial effects of Mg administration on thrombosis have also been shown in humans. Shechter et al.³⁰ reported that intravenous Mg therapy reduced mortality in thrombolysis-ineligible patients with AMI. Atherosclerosis Risk in Communities Study ³¹ suggested that low Mg levels might contribute toward the pathogenesis of coronary atherosclerosis or acute thrombosis.

Currently, Mg is not used routinely other than to increase serum Mg levels that are lower than 2.0 mg/dl in patients with AMI ¹¹. However, owing to the experimentally proven cardioprotective effects of Mg, promising results from animal studies, relatively low cost, and ease of administration, together with its generally good tolerability, it could be worthwhile to re-evaluate the potential therapeutic role of Mg in AMI and acute ST in larger well-designed, randomized-controlled clinical trials.

There are several limitations of this study. First, this study has a retrospective design. Second, intravascular ultrasound was not routinely used in patients with acute ST. This precluded the analysis of stent expansion and insufficient stent overlap. Third, although previous reports suggested that TIMI major bleeding was correlated with the development of ST ^32,33, no data were obtained for TIMI major bleeding. Fourth, we do not have data on platelet inhibition, although the importance of genetic constitution in relation to (on-treatment) platelet reactivity was confirmed by several recent studies showing that the carriage of CYP2C19*2 and CYP2C19*3 alleles is associated with an impaired response to clopidogrel and worse clinical outcome ³⁴. Finally, we did not perform serial Mg measurements or investigate whether a change in its levels was correlated with the risk of acute ST.

Conclusion

The results of the present study have suggested that measurement of serum Mg on admission may help to identify patients who are at risk of developing acute ST after p-PCI in STEMI patients.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.