Unstable angina and NSTEMI: early management

What the guideline recommends

CG167 currently makes no recommendations on the use of multivessel PCI in people with STEMI and multivessel coronary disease.

Methods

Wald et al. (2013) performed a multicentre RCT including 465 patients with STEMI treated by immediate multivessel PCI (n=234) or culprit-only primary PCI (PPCI; n=231).

Patients of any age with acute STEMI and multivessel coronary disease, identified at the time of emergency PCI, were included. They were considered eligible if the infarct artery was treated successfully but 1 or more coronary artery other than the infarct artery had greater than 50% stenosis and the stenosis was considered treatable by PCI. Patients with cardiogenic shock, a history of previous coronary artery bypass grafting (CABG), non-infarct-artery stenosis greater than 50% in the left main stem or the ostia of both the left anterior descending and circumflex arteries or non-infarct stenosis caused by chronic total occlusion were excluded. Patients were randomly allocated to receive no further treatment or to undergo preventative PCI in non-infarct arteries following PCI of the infarcted artery.

The primary outcome was the composite of cardiac-related mortality, non-fatal myocardial infarction, or refractory angina. Each outcome was also assessed separately. Secondary outcomes were all-cause mortality and the need for repeat revascularisation (PCI or CABG).

Results

Authors report that recruitment was stopped early due to recommendations from an overseeing committee which noted highly significant differences (p<0.001) between groups in favour of multivessel PCI. Patients were followed-up for a mean of 23 months: 67% of patients were followed-up for at least 1 year and 46% of patients were followed-up for at least 2 years. Ten patients in the multivessel PCI and 8 patients in the culprit-only PPCI group were lost to follow-up.

The primary outcome (composite of cardiac-related mortality, non-fatal myocardial infarction, or refractory angina) was reported in 21 out of 234 patients in the multivessel PCI group and 53 out of 231 patients in the culprit‑only PPCI group at follow-up (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.21 to 0.58; p<0.001). Significant differences in favour of multivessel PCI were still observed when analyses were limited to the composite of cardiac-related mortality and non-fatal myocardial infarction (HR 0.36; 95% CI 0.18 to 0.73; p=0.004). Authors reported that Kaplan–Meier analysis revealed that the risk reduction in the multivessel PCI group was evident within 6 months and maintained thereafter.

In relation to individual outcome measures, no significant differences in the risks of cardiac-related mortality (HR 0.34; 95% CI 0.11 to 1.08; p=0.07) and non-cardiac mortality (HR 1.10; 95% CI 0.38 to 3.18; p=0.86) were observed between groups at mean follow-up of 23 months. The rate of non-fatal myocardial infarction was 7 out of 234 patients in the multivessel PCI group and 20 out of 231 patients in the culprit-only PPCI group (HR 0.32; 95% CI 0.13 to 0.75; p=0.009). Refractory angina rates were reported in 12 out of 234 and 30 out of 231 patients in the multivessel and culprit-only PPCI groups, respectively (HR 0.35; 95% CI 0.18 to 0.69; p=0.002). Repeat revascularisation was needed in 6.8% (16/234) and 19.9% (46/231) of patients in the multivessel and culprit-only PPCI groups, respectively (HR 0.30; 95% CI 0.17 to 0.56; p<0.001). With respect to procedure-related adverse events, no significant differences in rates of procedure-related stroke, bleeding requiring transfusion or surgery and contrast-induced neuropathy requiring dialysis were observed between groups.

None of the reported outcome measures were significantly associated with age, sex, presence/absence of diabetes, infarct location or the number of coronary arteries with stenosis.

Strengths and limitations

Impact on guideline

Currently CG167 makes no recommendations on when to perform multivessel PCI. This study indicates that immediate multivessel PCI confers significant benefits over culprit-only PPCI in patients with STEMI. Topic experts stated that the question of when to use multivessel PCI or culprit-only PPCI is an important question in interventional cardiology. They suggested that the extensive use of multivessel PCI could have an impact on clinical practice. One expert highlighted that if practice changes high-risk groups may also change and the impact of these changes will need to be fully understood.

What the guideline recommends

CG167 currently makes no recommendations on the use of drug-eluting stents in people with STEMI.

Methods

Raber et al. (2014) performed a multicentre RCT including 1,116 patients with STEMI treated by biolimus-eluting stents with biodegradable polymer (n=575) or bare-metal stents (n=582).

Patients over 18 years with acute STEMI of more than 1 mm in greater than 2 contiguous leads, true posterior myocardial infarction, or new left bundle branch block were included. All patients had more than 1 culprit lesion within the infarct vessel. Exclusion criteria were presence of mechanical complications of acute STEMI, known allergy to any study medication, use of vitamin K-antagonists, history of bleeding diathesis or known coagulopathy, and non-cardiac comorbid conditions with life expectancy below 1 year.

Whenever feasible, manual thrombus aspiration was performed before stent implantation. Pre-dilation of the culprit lesion was left to the discretion of the operator. When available, prasugrel was used during and after PCI. If prasugrel was not available or contraindicated, clopidogrel was administered. Furthermore, patients received either unfractionated heparin or bivalirudin during treatment. Complete revascularisation of all lesions within the infarct vessel had to be performed with the randomly allocated stent. Following PCI, all patients received dual antiplatelet therapy for at least 1 year. The primary endpoint was the composite of death, target-vessel reinfarction, and ischaemia-driven target-vessel revascularisation.

Results

Patients were followed-up for up to 2 years: data were available for over 95% of patients from each group at final follow-up. The primary outcome (composite of cardiac-related mortality, target-vessel reinfarction and target-lesion revascularisation) was reported in 5.8% (33/575) of patients in the drug-eluting stent group and 11.9% (68/582) of patients in the bare-metal stent group (HR 0.48; 95% CI 0.31 to 0.72; p<0.001). The composite rate of all-cause mortality, any reinfarction and any revascularisation was 14.5% (82/575) of patients in the drug-eluting stent group and 19.3% (110/582) of patients in the bare-metal stent group (HR 0.73; 95% CI 0.55 to 0.97; p=0.03).

In relation to individual outcome measures, no significant differences in the risks of cardiac-related mortality (HR 0.69; 95% CI 0.37 to 1.27; p=0.23) and all-cause mortality (HR 0.79; 95% CI 0.53 to 1.46; p=0.62) were observed between groups at 2-year follow-up. Significantly fewer patients experienced target-vessel reinfarction in the drug-eluting stent group (1.3%; 7/575) compared to the bare-metal stent group (3.4%; 19/582), HR 0.37 (95%CI 0.15 to 0.87; p=0.023). No difference in the proportions of patients who had any reinfarction was observed between groups (HR 0.64; 95% CI 0.35 to 1.16; p=0.14). Ischaemia-driven target-lesion revascularisation was needed in 3.1% (17/575) of patients in the drug‑eluting stent group and 8.2% (46/582) of patients in the bare-metal stent group (HR 0.36; 95% CI 0.21 to 0.63; p<0.001). Similarly, significant differences in the occurrence of any target-lesion revascularisation were also observed between groups (HR 0.35; 95% CI 0.21 to 0.59; p<0.001). With respect to procedure-related adverse events, no significant differences in rates of procedure-related stroke and stent thrombosis were observed between groups.

Strengths and limitations

Impact on guideline

CG167 makes recommendations on PPCI using bare-metal stents in patients with STEMI but does not make any recommendations on PPCI using drug-eluting stents. Raber et al (2014) highlights the potential benefits of using contemporary drug-eluting stents over bare-metal stents in patients with STEMI. Topic experts highlighted that drug-eluting stent prices have decreased significantly since their initial introduction and felt that this may have cost implications on procurement. Experts also highlighted that there are various types of drug-eluting stents available and they may not have comparable safety and efficacy profiles.

What the guideline recommends

CG167 incorporates recommendations from NICE's technology appraisal guidance on bivalirudin for the treatment of ST-segment-elevation myocardial infarction:

1.2.2 Bivalirudin in combination with aspirin and clopidogrel is recommended for the treatment of adults with STEMI undergoing primary PCI.

Methods

Shahzad et al. (2014) performed an open-label RCT including 1,812 patients with STEMI who received bivalirudin or unfractionated heparin during PPCI.

Patients over 18 years with STEMI were enrolled unless they had intolerance, hypersensitivity, or contraindications to trial medications; active bleeding at presentation; artificial ventilation; reduced consciousness level or other factors precluding administration of oral antiplatelet therapy or their physician refused to administer antiplatelet loading. Patients were randomly allocated to groups at presentation, before entry to the catheterisation laboratory. Randomisation was stratified by age and presence of cardiogenic shock.

All patients received dual antiplatelet therapy before PPCI. Subsequently, patients received the assigned medication (bolus dose of 70U/Kg of heparin or 0.75mg/Kg of bivalirudin) after entry to the catheter laboratory but before angiographic findings were known. PPCI was performed by 1 of 14 interventional cardiologists who were blinded to treatment allocations. Primary outcome measures were the incidence of major bleeding as well as the composite rate of mortality, cerebrovascular accident, reinfarction and target- lesion revascularisation. Secondary outcome measures included minor bleeding, stent thrombosis and cardiac enzyme release. Analysis was performed using the intention-to-treat approach.

Results

Patients were followed-up for 28 days. The primary outcome (composite of mortality, cerebrovascular accident, reinfarction and target-lesion revascularisation) was reported in 8.7% (79/905) of patients in the bivalirudin group and 5.7% (52/905) of patients in the heparin group (risk ratio [RR] 1.52; 95% CI 1.09 to 2.13; p=0.01). In relation to individual major adverse cardiac events, no significant differences in mortality rates and cardiovascular accident rates were observed between groups. The incidence of new myocardial infarction or reinfarction was significantly higher in the bivalirudin group (RR 3.01; 95% CI 1.36 to 6.66; p=0.004). Additionally, the incidence of additional unplanned revascularisation was reported in 2.7% (24/905) of patients in the bivalirudin group and 0.7% (6/907) of patients in the heparin group (RR 4.01; 95% CI 1.65 to 9.76; p=0.001).

The risk of stent thrombosis was significantly higher in the bivalirudin group compared to the heparin group (RR 3.91; 95% CI 1.61 to 9.52; p=0.001). Similar rates of bleeding events were observed between groups. No significant differences in major and minor bleeding rates were observed between groups. Furthermore, no significant differences in thrombocytopenia rates and door to device times were reported between groups.

Strengths and limitations

Impact on guideline

The guideline states that bivalirudin in combination with aspirin and clopidogrel is recommended for the treatment of adults with STEMI undergoing PPCI. This study suggests that unfractionated heparin confers better outcomes than bivalirudin. Topic experts stated that this study was the first study to compare bivalirudin and heparin with equal use of GPI inhibitors in both study arms.