Non-ST-segment elevation acute coronary syndrome (NSTEACS) includes unstable angina pectoris (UAP) and non-ST-segment elevation myocardial infarction (NSTEMI), which was previously referred to as non-Q-wave myocardial infarction (NQMI). It is an incomplete occlusive thrombus in the infarct-related artery caused by an unstable atherosclerotic plaque, and is a platelet-based “white thrombus” formation, unlike the intracoronary occlusive “red thrombus” of ST-segment elevation acute coronary syndrome. Therefore, the treatment strategy of NSTEACS is very different from that of STEACS.
1. Risk stratification of non-ST-segment elevation acute coronary syndromes
1.1 Risk stratification model
The clinical presentation, treatment and prognosis of non-ST-segment elevation acute coronary syndrome ( UA/ NSTEMI ) vary with the early risk factor classification. Accurate risk stratification of patients at an early stage can help to select the most appropriate treatment and thus improve the prognosis. The TIMI risk score was generated in the TIMI 11B trial. Its seven predictors are.
(1) Age ≥ 65 years;
(2) Presence of at least three risk factors for coronary artery disease (family history, diabetes, hypertension, hypercholesterolemia, smoking);
(3) significant coronary stenosis (known coronary stenosis ≥ 50%);
(4) ST-segment depression;
(5) severe angina symptoms (angina ≥ 2 times in 24 hours);
(6) aspirin application within 7 days;
(7) elevated cardiac enzymes (CK-MB and/or myocardial-specific troponin).
The TIMI risk score is simple, practical, and has been prospectively validated, with the disadvantage that the degree of coronary stenosis is not easily determined at the time of presentation. The higher the TIMI score, the greater the risk of cardiovascular events in the patient. The risk of cardiovascular events in patients with a TIMI score of 0 to 1 is 4.7%, while the risk increases to 40.9% with a TIMI score of 6 to 7.
In addition to the TIMI risk score, early risk stratification models include the RUSH model, the AHCPR model, and the PURSUIT trial published in 2000, which analyzed a series of risk predictors for NSTEACS. In 2002, the ACC/AHA developed risk stratification guidelines for NSTEACS based on risk factors confirmed by available clinical trials. These risk stratification models are useful in guiding the treatment of NSTEACS.
1.2 Risk stratification indicators
Myocardial-specific troponin is an important basis for risk stratification of patients presenting to the emergency department with chest pain. Patients with non-ST-segment elevation in acute coronary syndromes with elevated troponin T have been shown to have a higher rate of recurrent myocardial infarction and sudden death.
Recent studies have shown that treatment with platelet membrane glycoprotein IIb/IIIa receptor blockers and low-molecular heparin is more effective in patients with NSTEACS with elevated troponin T than in patients with NSTEACS with negative troponin T. Coronary endoscopy confirmed that the presence of intracoronary thrombus is an independent risk factor for troponin T elevation in patients with NSTEACS. Therefore, troponin T elevation is an important indicator of poor prognosis in patients with NSTEACS.
Morono et al. compared stable angina pectoris (SAP) and UAP coronary atheromatous plaque specimens and found that macrophages and lymphocytes were abundant and activated in the plaques of UAP patients, suggesting that the formation of coronary atheromatous plaques in UAP patients may be related to the inflammatory response. Elevated systemic acute phase response inflammatory markers such as C-reactive protein (C-RP) and fibrinogen levels have been reported as independent predictors of acute coronary syndromes.
Recent studies have shown that Brian natriuretic peptide (BNP) plays an important role in the early risk stratification of patients with NSTEACS, and that blood levels of BNP and NT-proBNP are strongly correlated with the morbidity and mortality and the development of congestive heart failure in patients with NSTEACS.
2. Coronary angioplasty
After appropriate risk stratification of patients, appropriate treatment can be developed. Early invasive treatment is advocated for high-risk to intermediate-risk patients, while non-invasive stress tests are advocated for low-risk patients.
2.1 Early interventional treatment
The first large multicenter, randomized controlled trial TIMI III B, which began in October 1989 to study the effects of early intervention and conservative treatment, showed that direct intervention did not reduce mortality or the incidence of myocardial infarction in unstable angina/non-Q-wave myocardial infarction. The subsequent VANQWISH and MATE trials also failed to find a superiority of early intervention.
However, FRISC II, TACTICS-TIMI 18, RITA3, and ISAR-COOL showed that early intervention was superior to conservative treatment. A total of 1810 patients with non-ST-segment elevation acute coronary syndromes were enrolled in the RITA3 trial and randomized to the early intervention and conservative treatment groups, with enoxaparin administered in both groups. The composite endpoint events were death, non-fatal myocardial infarction within 1 year, and recurrent angina within 4 months.
The results revealed that within 4 months, 86 ( 9.6%) of the early intervention group had a composite endpoint event; while 133 ( 13.3%) of the conservative treatment group had a composite endpoint event (OR0.66, p=0.001). This difference was mainly due to the fact that early intervention reduced the incidence of recurrent angina by half. The incidence of death and myocardial infarction within one year was 68 (7.6%) and 76 (8.3%) in the two groups, respectively (OR0.91, p=0.58).
Thus, early intervention is preferable to conservative treatment in non-ST-segment elevation acute coronary syndromes mainly because it leads to a significant reduction in the incidence of recurrent angina without increasing the incidence of death or myocardial infarction.
The FRISC II trial found that early intervention improved health-related quality of life within one year of onset. In TACTICS-TIMI 18, UA/NSTEMI patients were classified into low-risk ( 0 – 2), intermediate-risk ( 3 – 4), and high-risk groups ( 5 – 7) according to the TIMI risk score.
Statistical results showed that the effectiveness of early intervention was highly correlated with the TIMI risk score: early intervention did not show significant superiority in the low-risk group, and early coronary intervention + stenting with intravenous platelet membrane glycoprotein IIb/IIIa receptor antagonist tirofiban and aspirin, heparin, and β-R blockers was superior to early treatment in the intermediate-risk and high-risk groups. Conservative regimens (aspirin, heparin, β-R blockers and tirofiban) are preferable to early treatment. Therefore, a proper assessment of the patient at the time of admission is particularly important to guide the development of an optimal treatment plan.
Analysis of the subgroup with elevated cTNT showed that the incidence of cardiovascular events (death, myocardial infarction, rehospitalization for acute coronary syndrome) at month 6 was 40% lower in patients who received early intervention than in those who did not receive early intervention. There was no significant benefit of early intervention in the subgroup of patients with normal cTNT.
Therefore, patients with NSTEACS with elevated troponin should be treated early with platelet membrane glycoprotein IIb/IIIa receptor antagonists and conventional aspirin, heparin, and β-R blockers; early intervention should be avoided in low-risk patients without high troponin.
2.2 New advances in drug-coated stents
Currently, coronary balloon dilation and stenting have become important treatments for coronary artery disease, but some patients recur within 6-9 months after surgery, with restenosis rates as high as 10-40%. In recent years, the widespread use of drug stents has led to a significant reduction in the rate of in-stent restenosis after surgery (5%), and many different types of drug-coated stents have emerged.
Rapamycin and its derivatives, paclitaxel and its derivatives, and actinomycin D can be used to make drug-coated stents. Many large clinical trials have shown that drug stents can significantly reduce the incidence of in-stent restenosis from the beginning of simple primary coronary lesions to high-risk complex patients with long lesions, small-vessel lesions, in-stent restenosis, and concomitant diabetes mellitus.
FUTURE I was a single-center, single-blind randomized trial evaluating the safety and feasibility of everolimus-releasing stents in 15 patients with bare stents and 27 patients with everolimus-coated stents, with no major adverse cardiac events (MACE) within 30 days in either group; late lumen loss at 6 months was 0.10 mm in the drug stent group and 0.83 mm in the bare stent group.
FUTURE II, a multicenter randomized trial, enrolled 64 patients with late lumen loss of 0.12 mm in the drug stent group and 0.85 mm in the bare stent group at 6 months. These trials demonstrated the superiority of pharmacological stents in preventing restenosis.
3. Pharmacological treatment of NSTEACS
Vikman S et al. compared the FINACS I and FINACS II trials, which were conducted in the same hospitals and had similar patient enrollment criteria and study methods, but due to the widespread use of statins, ACEI, clopidogrel, and platelet membrane glycoprotein IIb/IIIa receptor antagonists in patients with NSTEACS in the FINACS II trial, and the widespread use of angioplasty (see Fig. 3), the trial was conducted in the same hospitals. The widespread use of angioplasty (especially in high-risk patients) has led to a significant increase in survival during hospitalization and within 6 months in high-risk patients. Therefore, drug therapy is as important as interventional therapy.
3.1 Antiplatelet agents for NSTEACS
3.1.1 Cyclooxygenase inhibitors
Aspirin is the most widely used antiplatelet drug, and its main mechanism of antiplatelet is to inhibit cyclooxygenase, which prevents the derivation of AA to TXA2. Inactivation of cyclooxygenase acetylation is not compensated for during platelet survival, and therefore the antiplatelet activity of small daily oral doses of aspirin has a cumulative effect. In five placebo-controlled and double-blind clinical studies published from 1983 to 1991 with a total of more than 3000 patients, aspirin significantly reduced the incidence of AMI and sudden death in patients with unstable angina.
The RISC trial reported that aspirin was significantly more effective than heparin in unstable angina and that the combination of the two drugs was superior to aspirin alone. Today, with the widespread use of aspirin, there is a phenomenon of aspirin “escape”, which is now considered to be a form of aspirin resistance.
3.1.2 Platelet membrane glycoprotein IIb/IIIa receptor antagonists
Fibronectin and other adhesion proteins link adjacent platelets through IIb/IIIa receptors, so platelet membrane glycoprotein IIb/IIIa receptor antagonists are effective in inhibiting platelet aggregation, reducing the incidence of various ischemic events and reducing mortality and myocardial infarction in patients with NSTEACS. Tirofiban is a chemically synthesized small molecule mimetic peptide that competitively inhibits platelet aggregation mediated by fibrinogen or vWF.
The PRISM-PLUS trial demonstrated that in patients with NSTEACS with a TIMI risk score ≥4 and without PCI, the rates of death, myocardial infarction, and recurrent ischemia were 28.8% vs. 21.9% (OR0.69, p = 0.04) within 30 days of treatment of NS TEACS with tirofiban + heparin versus heparin alone;
In patients with NSTEACS with a TIMI risk score ≥4 and PCI, the rates of death, myocardial infarction, and recurrent ischemia within 30 days for NSTEACS treated with tirofiban + heparin versus heparin alone were (32.4% vs 22.2%; OR 0.60, p = 0.06). There was no significant difference in the rate of the composite endpoint event between the two groups in patients at low risk for the TIMI risk score.
Abciximab is a platelet membrane glycoprotein IIb/IIIa monoclonal antibody that has a high affinity for the receptor and irreversibly inhibits platelet aggregation in a dose-dependent manner. Platelet membrane glycoprotein IIb/IIIa receptor antagonists have been reported to reduce thrombotic complications while also increasing the risk of bleeding in various organs.
In the GUSTO IV-ACS trial, 7800 patients with ACS were enrolled and randomized to the abciximab and placebo groups. Bleeding events occurred in 1507 patients (19.3%) within 7 days, with 98 (1.2%) experiencing major organ bleeding, including 8 cerebral bleeds. Compound bleeding occurred in 911 (11.7%) patients. The results suggest that although abciximab may increase the risk of bleeding from all organs in patients with NSTEACS, most bleeding events were mild and did not have serious consequences. Therefore, abciximab is safe for the treatment of NSTEACS.
3.1.3 Platelet membrane ADP receptor inhibitors
The platelet membrane ADP receptor inhibitors currently in clinical use are ticlopidine and clopidogrel, both of which belong to the thienopyridine class of compounds. Clopidogrel inhibits platelet membrane ADP receptors about 30 times more strongly than ticlopidine, reduces blood fibrinogen levels and viscosity, and has anticoagulant effects. In the CURE trial, 12562 patients with non-ST-segment elevation acute coronary syndrome were randomized to clopidogrel + aspirin and placebo + aspirin groups.
The observed endpoint events were: cardiovascular death, myocardial infarction, and stroke. Statistical results confirmed a durable benefit in the clopidogrel+aspirin group in patients undergoing percutaneous coronary intervention, with an incidence of cardiac endpoint events of 9.6%, 13.2%, and RR0.72 in the two groups, respectively; in patients undergoing coronary artery bridging, the incidence of cardiac endpoint events in the clopidogrel+aspirin and placebo+aspirin groups were 14.5%, 16.2%, and RR0.89, respectively; and in patients undergoing coronary artery bridging, the incidence of cardiac endpoint events in the clopidogrel+aspirin and placebo+aspirin groups was 14.5%, 16.2%, and RR0.89. RR0.89 ;
Before coronary artery bridging, the incidence of cardiac endpoint events in the two groups was 2.9%, 4.7%, and RR0.56, respectively; in patients treated with medication alone, the incidence of cardiac endpoint events in the two groups was 8.1%, 10.0%, and RR0.80, respectively. Throughout the trial, there was only a 1% bleeding rate, but none was life-threatening. Among patients treated with CABG, the percentages of life-threatening bleeding events in the clopidogrel+aspirin and placebo+aspirin groups were 5.6% and 4.2%, respectively, with an RR of 1.30.
Thus, the CURE trial confirmed that clopidogrel, while increasing the risk of bleeding to some extent, significantly reduced the incidence of cardiac endpoint events. All patients undergoing angioplasty (CABG or PCI) benefit from early and long-term use of clopidogrel. Even in patients who will undergo CABG, the benefits of clopidogrel outweigh the risks of bleeding.
3.2 Prothrombin inhibitors
3.2.1 Indirect thrombin inhibitors
Low-molecular-weight heparin (LMWH) is an indirect inhibitor of thrombin. Its anti-factor Xa activity is greater than that of anti-factor IIa, thus its anti-thrombotic effect is better than that of heparin, while its anticoagulant effect is weaker than that of heparin, resulting in less complicated bleeding in clinical application. LMWH is easy to use by subcutaneous injection, has a long duration of action and high bioavailability, does not require monitoring of clotting time, and does not produce thrombocytopenia caused by common heparin, and is superior to common heparin in the treatment of NSTEACS.
Okmen E et al. looked at 68 patients with high-risk unstable angina treated with enoxaparin and nadroparin in combination with tirofiban, and showed that the incidence of primary endpoint events was similar in patients with high-risk unstable angina treated with both low-molecular-weight heparins in combination with tirofiban.
A total of 302 patients with UA/NQMI were enrolled in the Angiofrax trial, which involved 27 centers in 7 European countries, and were given intravenous 86 anti-XaIU/kg of nadroparin followed by subcutaneous nadroparin 86 anti-XaIU/kg twice a day during the perioperative period and aspirin during PCI. UFH100IU/kg was given during PCI. The primary endpoint event was defined as a bleeding event during treatment and the secondary endpoint was defined as the incidence of coronary thrombotic events during the 6-day treatment period.
The results of the study showed that the anticoagulation regimen of 86 IU/kg of nadroparin administered intravenously first during the acute phase of UA or NQMI, UFH substituted during coronary angiography or PCI, and subcutaneous nadroparin administered every 12 hours after the procedure, with at least 8 hours between the last nadroparin injection and the start of the coronary intervention, regardless of whether or not PCI was performed after coronary angiography, was a good solution for patients who were also receiving aspirin. This anticoagulation regimen is safe for patients receiving aspirin at the same time. Most bleeding events were small and occurred mainly at the puncture site, with a low incidence of major bleeding (1.3%).
The NICE-3 study combined enoxaparin with any one of tirofiban, abciximab, or etefibatide for NSTEACS. The primary endpoint events were: major bleeding events not related to CABG, death, myocardial infarction, and immediate angioplasty for reischemia. Enoxaparin was administered to 671 patients, of whom 628 were treated with any of the IIb/IIIa receptor antagonists (tirofiban, n = 229; etefibatide, n = 272; abciximab, n = 127).
Based on a comparison of the incidence of primary endpoint events during hospitalization and within 30 days, it was concluded that the combination of enoxaparin and platelet membrane glycoprotein IIb/IIIa receptor antagonists was safe for the treatment of NSTEACS and that no additional heparin was required during treatment.
3.2.2 Direct thrombin inhibitors
Direct inhibitors of thrombin inhibit not only free thrombin but also fibrin-bound thrombin. Hirudin is a specific inhibitor of thrombin, which has an inhibitory effect on thrombin-induced platelet aggregation, has no effect on platelet function, does not cause a decrease in platelets in peripheral blood, and is suitable for those who have a reduced number of platelets and need anticoagulation therapy.
Recombinant lepirudin is also a specific inhibitor of thrombin, and the OASIS-2 study showed that lepirudin (recombinant lepirudin) was more effective than heparin in patients with NSTEACS on top of aspirin, and there was a significant difference in the incidence of major endpoint events between the two groups within 7 days, although the rates of mild and severe bleeding were higher than those of heparin. The rate of minor and major bleeding was higher than that of heparin.
3.3 Statins
In recent years, many studies have shown that statins can promote apoptosis of vascular smooth muscle cells, prevent intimal thickening and foam cell formation, stabilize and reduce the size of atherosclerotic plaques, inhibit the adhesion of monocytes to endothelial cells, weaken the secretion function of monocytes-macrophages, reduce plasma C-reactive protein, and inhibit the inflammatory response of the atherosclerotic process. It inhibits platelet aggregation and increases fibrinolytic activity, and blocks thrombosis.
The MIRACL trial was a randomized, double-blind clinical trial involving 122 clinical centers. 3086 patients with UP/NQMI were enrolled and randomized to the atorvastatin and placebo groups. The incidence of the primary endpoint in the two groups was 14.8 percent and 17.4 percent, respectively, P=0.048. The risk of symptomatic myocardial ischemia requiring emergency readmission was reduced ( 6.2%, 8.4%, P = 0.02), while the risk of death, nonfatal AMI, and cardiac arrest did not differ significantly between the two groups.
In conclusion, before treating non-ST-segment elevation acute coronary syndrome ( NSTEACS ), patients should be clinically risk stratified and treatment strategies should be tailored to their specific conditions. Combining interventional, surgical and pharmacological treatments, strengthening the prevention of coronary artery disease, and paying attention to inpatient treatment and post-discharge treatment and follow-up.