Background
Methods
Eligibility criteria
Data source and searches
Selection of studies
Data extraction and risk of bias assessment
Certainty of evidence
Data synthesis and statistical analysis
Results
Selection of titles
Study characteristics
Author, year | Location | No. patient | Mean age (SD) | No. male (%) | Inclusion criteria | Exclusion criteria | Follow-up time (months) | Outcomes evaluated |
---|---|---|---|---|---|---|---|---|
ADMIT [28] | Haifa, Israel | 100 | I = 57.5 (12.4) | 86 (86.0) | Admission <12 hours of onset of symptoms of STEMI, regardless of the initial TIMI flow | Inability to consent; known allergy to either aspirin or clopidogrel; life expectancy <6 months; cardiogenic shock | 6 months | Quality of epicardial and microcirculation perfusion; LV function; ischemic mitral regurgitation; MACE (death, recurrent MI, TVR) |
C = 57.2 (12.1) | ||||||||
Bulum 2012 [29] | Zagreb, Croatia | 60 | I = 54.3 (9.7) | 47 (78.3) | Symptoms suggesting acute myocardial ischemia of >20 min, time from symptom onset of <12 hours, and ST-segment elevation >0.1 mV in >2 contiguous ECG leads | Need for rescue PCI after failed thrombolysis; cardiogenic shock; triple-vessel disease; significant LMCA stenosis; previous PCI of an IRA; previous CABG; life expectancy <6 months | 6 months | Referent vessel diameter; minimal lumen diameter; lesion length; percentage of diameter stenosis; MACE (death, recurrent MI, stroke, TLR) |
C = 58.5 (8.6) | ||||||||
Chao 2008 [30] | Taipei City, Taiwan | 74 | I = 60 (13) | 63 (85.1) | STEMI (typical chest pain >30 min with new ST-segment elevation ≥0.1 mV in >2 contiguous leads on a 12-lead ECG), <12 hours after onset, and eligible for primary PCI | Killip IV hemodynamic status; ventricular tachyarrhythmias; previous CABG or significant LMCA lesion; culprit vessel diameter <2 mm; existing TIMI 3 flow without visible thrombus in IRA | 6 months | Angiographic differences in TIMI and MBG (post PCI - baseline); MACE (death, stroke, non-fatal recurrent MI, TVR) |
C = 62 (11) | ||||||||
De Luca 2006 [31] | Rome, Italy | 76 | I = 66.7 (14.1) | 48 (63.2) | Anterior STEMI, >18 years old, and have an identifiable thrombus on IRA at coronary angiography | Previous MI or CABG; triple-vessel disease; severe valvar disease; TIMI 2 or 3 flow at the time of initial angiography; unsuccessful PCI defined as no antegrade flow or >50 % residual stenosis in the IRA | 6 months | LV remodeling; MACE (death, recurrent MI, hospitalization for HF) |
C = 64.6 (12.5) | ||||||||
Rome, Italy | 175 | I = 66.7 (14.1) | 105 (60.0) | First STEMI, <9 hours from symptoms onset, IRA ≥2.5 mm in diameter, thrombus score ≥ 3, TIMI flow ≤1, and >18 years old | Previous PCI on IRA; previous CABG; cardiogenic shock; triple-vessel disease; LMCA disease; severe valvular disease; thrombolysis; contraindication to glycoprotein IIb/IIIa inhibitors | 9 months | Final MBG ≥2; rate of 90-min ST-segment resolution >70 %; MACE (cardiac death, recurrent MI, TVR); stent thrombosis | |
C = 64.6 (12.5) | ||||||||
EXPORT [34] | 24 centres in India and Europe | 249 | I = 59.2 (12.8) | 202 (81.1) | >18 years old, STEMI <12 hours of symptom onset, ST-segment elevation ≥2 mm in ≥2 contiguous leads, visual reference vessel diameter >2.5 mm, and with TIMI flow of 0 or 1 before placing the wire in the IRA | Cardiogenic shock; cardiac arrest prior to intervention; pre-catheterization therapy with lytic agents, or with glycoprotein IIb/IIIa inhibitors, or with pacemakers; life expectancy <1 year; current participation in other investigations | 1 month | Reperfusion (rate of ST-segment resolution >50 % at 60 minutes postprocedure or MBG 3 immediately postprocedure); magnitude of ST-segment resolution; improvement in TIMI flow; corrected TIMI frame count; MACE (death, recurrent MI, emergent CABG, TLR or TVR, stroke); rate of distal embolization; rate of required bailout techniques (rescue use of the aspiration catheter, distal protection, or glycoprotein IIb/IIIa inhibitors) |
C = 61.2 (12.9) | ||||||||
IMPACT [35] | Cambridge, UK | 56 | I = 64.9 (11.2) C = 67.2 (11.6) | 31 (55.3) | >18 and <90 years old, ability to give informed consent, STEMI (ST-segment elevation ≥2 mm in ≥2 contiguous chest leads or ≥1 mm in ≥2 contiguous limb leads) or new LBBB, chest pain for <12 hours, restoration of at least TIMI 1 flow after the wire crossed the occlusion | Cardiogenic shock; previous MI in the IRA territory; unfavourable anatomy (LMCA occlusion or distal vessel occlusion); severe asthma or bradycardia precluding use of adenosine; women of childbearing age; life expectancy <3 months | 6 months | Index of microcirculatory resistence; MACE (all-cause death or MI) |
37 sites in 6 countries | 452 | I = 61 (NR) | 334 (73.9) | ≥18 years old, STEMI with ≥1 mm of ST-segment elevation in ≥2 contiguous leads in V1 through V4 or new LBBB with anticipated symptom onset to device time of ≤5 hours | Prior MI, CABG or LAD stenting; contraindications to study medications, contrast or CMRI; creatinine clearance <30 mL/min per 1.73 m2 or dialysis; platelet count <100,000 or >700,000 cells/mm3; hemoglobin <10 g/dL; recent major bleeding; bleeding diathesis; current warfarin use; intracranial disease, stroke or TIA within 6 months or any neurological defect; cardiogenic shock; prior fibrinolysis or glycoprotein IIb/IIIa inhibitors for the present admission; any comorbid likely to interfere with protocol compliance or associated with <1 year survival | 12 months | Infarct size measured as a percentage of LV mass at 30 days. MACE (death, recurrent MI, new-onset severe HF, re-hospitalization for HF, stroke, clinically driven TVR) | |
C = 60 (NR) | ||||||||
ITTI [38] | Kaohsiung City, Yun-Lin Branch, Taiwan | 100 | I = 60.4 (11.9) | 86 (86.0) | ≥18 years old, continuous chest pain ≥30 min, ST-segment elevation >0.1 mV in ≥2 contiguous leads on a 12-lead ECG | Cardiogenic shock (systolic BP > 80 mmHg or need for inotropic agent); history of bleeding tendency, major operation within 6 weeks; hepatic or renal insufficiency; contraindication to tirofiban use | 6 months | Occurrence of MBG 3; complete ST-segment resolution; procedure time; occurrence of no-reflow; CK-MB peak and time to peak; TIMI flow and corrected TIMI frame count; MACE (death, recurrent MI, TLR, stroke) |
C = 56.5 (11.9) | ||||||||
Kaltoft 2006 [39] | Aarhus, Denmark | 215 | I = 65 (11) | 168 (78.1) | STEMI, symptoms lasting >30 min but <12 hours, and cumulative ST-segment elevation of ≥2 mV in ≥2 contiguous leads | LBBB; MI within the previous 30 days; fibrinolytic treatment; previous CABG; LCA stenosis; need for mechanical ventilation; severe HF treated with intra-aortic balloon pump | 1 month | Myocardial salvage estimated by 99mTc-sestamibi SPECT; final infarct size; markers of effective reperfusion (TIMI flow, corrected TIMI frame count, ST-segment resolution immediately, 90 min and 6 hours after PCI); release of TnT; distal embolization visible at the end of PCI; total procedure time; MACE (death, recurrent MI, disabling stroke); LVEF after 30 days; technical success of the thrombectomy |
C = 63 (13) | ||||||||
Liistro 2009 [40] | Arezzo, Italy | 111 | I = 64 (11) | 86 (77.5) | STEMI with symptoms lasting >30 minutes and <12 hours, ST-segment elevation >0.1 mV in ≥2 leads on the ECG | Contraindication to the use of platelet glycoprotein IIb/IIIa inhibitors; rescue PCI after thrombolysis; previous MI; absence of optimal echocardiographic apical view; life expectancy <6 months; lack of informed consent | 6 months | Rate of ST-segment resolution ≥70 %; TIMI 3 grade flow; corrected TIMI frame count; myocardial contrast echocardiography score index; absence of persistent ST-segment deviation; time course of wall-motion score index; LVEF; LV volume; death; recurrent MI; LV failure; new revascularization |
C = 65 (11) | ||||||||
REMEDIA [41] | Rome, Italy | 99 | I = 61 (13) | 83 (83.3) | <12 hours of onset of STEMI referred for primary or rescue PCI | No angiographic exclusion criteria were adopted | 1 month | MBG ≥2; rate of ST-segment resolution ≥70 %; peak CK-MB; direct stenting rate; distal embolization rate (abrupt “cutoff” occlusion of a distal branch); composite of distal embolization, slow-flow (TIMI flow grade 2), no-reflow (TIMI flow grade 0 to 1); death; recurrent MI; stroke; TLR; any major adverse event |
C = 60 (13) | ||||||||
Shehata 2014 [25] | Cairo, Egypt | 100 | I = 60.32 (9.2) | 64 (64) | Diabetic patients suffering from acute STEMI, symptoms lasting >30 minutes and <12 hours before admission, and ST-segment elevation of >0.1 mV in ≥2 leads | Need for rescue PCI after thrombolysis; prior history of unstable angina or MI; prior PCI CABG; congenital heart disease or any myocardial disease apart from ischemia; limited life expectancy due to coexistent disease | 8 months | In-stent restenosis (angiographic luminal diameter stenosis by >50 % in quantitative coronary angiography); MACE (death due to cardiac cause, nonfatal MI, TLR) |
C = 59.4 (7.4) | ||||||||
Sim 2013 [42] | Gwangju, Republic of Korea | 86 | I = 63 (NR) | 59 (71.1) | STEMI with onset of symptoms <12 hours, coronary artery lesions with visible thrombus, ability to undergo a complete CCT examination (Killip I and II) with the ability to perform a15-second breath-hold | Previous MI or CABG; cardiogenic shock; LMCA disease; severe valvular heart disease; unsuccessful PCI (post-PCI TIMI flow <2 or ≥50 % residual stenosis in IRA); rescue or facilitated PCI; contraindication to glycoprotein IIb/IIIa inhibitors | 12 months | Infarct size at 2 months; markers of myocardial reperfusion (TIMI flow, MBG, ST-segment resolution rate at 90 min); LV function and volumes at 2 months; MACE (cardiac death, MI, TVR) |
C = 60(NR) | ||||||||
Groningen, The Netherlands | 1071 | I = 63 (13) | 755 (70.5) | STEMI, symptoms >30 minutes and <12 hours, and ST-segment elevation of ≥0.1 mV in ≥2 leads | Rescue PCI after thrombolysis; life expectancy <6 months; lack of informed consent | 1 month | Rate of post-procedural MBG of 0; rate of TIMI flow grade of 3; complete resolution of ST-segment elevation; absence of persistent ST-segment deviation; TVR; recurrent MI; death | |
C = 63 (13) | ||||||||
29 centers in Sweden, 1 center in Iceland and 1 in Denmark | 7244 | I = 66.5 (11.5) | 5424 (74.9) | STEMI, chest pain for >30 minutes and <24 hours, ST-segment elevation in ≥2 contiguous leads (≥0.2 mV in lead V2 or V3 or ≥0.1 mV in other leads) or a presumably new LBBB, and a corresponding culprit-artery lesion on angiography | Need for emergency CABG; inability to provide oral informed consent; <18 years old; previously randomized in the study | 12 months | MACE (all-cause mortality; rehospitalization for MI; stent thrombosis); TVR; TLR; complications of PCI, stroke or neurologic complications, HF and length of stay during index hospitalization | |
C = 65.9 (11.7) | ||||||||
TOTAL [6] | 87 hospitals in 20 countries | 10732 | I = 61.0 (11.8) | 7797 (72.6) | Symptoms of MI lasting for ≥30 min, definite ECG changes indicating STEMI, referred for PCI for presenting symptoms, randomized within 12 hours of symptoms onset and before diagnostic angiography, Informed consent | ≤18 years old; prior CABG; life expectancy <6 months due to noncardiac condition; treatment with fibrinolytic therapy for qualifying index STEMI event | 6 months | MACE (cardiovascular death, recurrent MI, cardiogenic shock, HF NYHA class IV); stroke |
C = 65.0 (11.9) | ||||||||
5 european centres | 141 | I = 61.1 (11.8) | 102 (72.3) | ≥18 years old, STEMI documented with ≥2 mm ST-segment elevation in ≥2 contiguous leads prior to PCI, presenting in the cath lab <12 hours after the onset of symptoms lasting ≥20 min and having an angiographically visible stenosis (>30 %) or TIMI ≤ II in a single de novo, native, previously unstented vessel | Pregnancy; known intolerance to aspirin, clopidogrel, heparin, stainless steel, limus drugs, contrast material; diameter stenosis <30 % in the target lesion; multi-vessel CAD; unprotected LMCA stenosis >30 %; distal vessel occlusion; severe tortuous, calcified or angulated anatomy that would result in sub-optimal imaging or excessive risk of complication from insertion of catheter; fibrinolysis prior to PCI; platelet <100,000 cells/μl; coagulopathy or active bleeding or chronic anticoagulation therapy; cardiogenic shock; significant comorbidities precluding follow-up as judged by investigators; major planned surgery requiring discontinuation of antiplatelets; proximal RCA stenosis (>30 %) if the IRA is mid or distal-RCA | 12 months | Minimum flow area immediately after PCI assessed by OFDI; MACE (cardiac death, recurrent MI in the territory of IRA, clinically driven TVR) | |
C = 60.9 (12.7) | ||||||||
VAMPIRE [47] | 23 hospitals in Japan | 355 | I = 63.2 (10.6) | 281 (79.1) | ≥21 years old, STEMI symptom >30 min but <24 hours, ST-segment elevation ≥2 mm in ≥2 contiguous leads or with a presumably new LBBB | Primary thrombolysis prior to randomization; cardiogenic shock; history of cardiac arrest; history of CABG; chronic renal failure (Cr >2.0 mg/dl) or hemodialysis; LMCA disease; target vessel <2.5 mm or >5 mm in diameter | 8 months | Incidence of slow flow or no reflow during primary PCI (TIMI flow grade <3 not attributable to dissection, occlusive thrombus, or epicardial spasm); coronary flow and myocardial perfusion immediately after PCI (assessed by TIMI flow grade, corrected TIMI frame count and MBG); magnitude of ST-segment resolution, peak CK and CK-MB; angiographic in-stent late lumen loss; LV function; brain natriuretic peptide; MACE (death, recurrence MI, TLR) |
C = 63.5 (9.9) | ||||||||
Yin 2011 [48] | Dalian, China | 164 | I = 63.1 (12.9) | 120 (73.2) | STEMI patients who had PCI | Not reported | 12 months | Thrombus score; periprocedural no-reflow; TIMI frame count; lumen diameter; stent length; 1-week post-procedural ejection fraction; post-procedural angina; recurrent MI; death |
C = 62.9 (9.5) |
Author, year | Different regimens of anti-aggregation/anticoagulation used |
---|---|
ADMIT [28] | Oral aspirin 300 mg as a loading dose (or only 100 mg if the patient was on aspirin therapy) continued by 100 mg/day indefinitely, 600 mg clopidogrel loading dose continued by 75 mg/day for one year and IV 60 mg/ kg unfractionated heparin as loading dose to keep activating clotting time during procedure > 250 second. |
Bulum 2012 [29] | 300 mg of aspirin and 600 mg of clopidogrel and a weight-adjusted dose of unfractionated heparin; the usage of glycoprotein IIb/IIIa inhibitor (eptifibatide) was left to the discretion of the operator. |
Chao 2008 [30] | Aspirin 300 mg and clopidogrel 300 mg were given as loading dose, with intravenous heparin 70– 100 U/kg to achieve activated clotting time (ACT) > 200 s prior to intervention. |
De Luca 2006 [31] | Aspirin 300 mg orally and heparin 8000 IU intravenously before the procedure and abciximab as a 0.25 mg/kg bolus and 0.125 mg/kg/min intravenous infusion immediately before the revascularisation and continued for 12 hours. |
Aspirin 300 mg, intravenous heparin, abciximab at a standard dose, and clopidogrel 300 mg before the revascularization. | |
EXPORT [34] | The choice of medication during the procedure such as aspirin, heparin, clopidogrel, and glycoprotein IIb/IIIa inhibitors was also at the investigator’s discretion, and were administrated according to standard hospital procedure. |
IMPACT [35] | Aspirin 300 mg and clopidogrel 600 mg preloading in the ambulance and anticoagulated with a heparin bolus (70–100 U/kg) after arterial sheath insertion to achieve an activated clotting time (ACT) >250 s. Adjunctive pharmacotherapy, including abciximab and bivalirudin, was given at the operator’s discretion. |
Patients undergoing primary PCI received bivalirudin anticoagulation. | |
ITTI [38] | Aspirin (300 mg loading followed by 100 mg daily) and clopidogrel (300 mg loading followed by 75 mg daily) and unfractionated heparin 100 IU/kg. |
Kaltoft 2006 [39] | Aspirin 300 mg orally or intravenously, clopidogrel 300 mg orally, and unfractionated heparin 10 000 IE intravenously. During the intervention, all patients were treated with abciximab. |
Liistro 2009 [40] | Aspirin (a loading dose of 500 mg), heparin (70 IU/kg), and clopidogrel (a loading dose of 600 mg). All patients also received the glycoprotein IIb/IIIa inhibitor abciximab with an intravenous procedural bolus of 0.25 mg/kg followed by a continuous intravenous infusion of 0.125 μg/kg/min for 12 hours and postprocedural infusion without heparin. |
REMEDIA [41] | Heparin (initial weight-adjusted IV bolus then further boluses administered with the aim of obtaining an activated clotting time of 250 to 300 s in patients treated with abciximab and > 300 s in the remaining subjects) and with double antiplatelet therapy with aspirin and clopidogrel (loading dose of 300 mg followed by 75 mg/day) for at least four weeks. Unless contraindicated, abciximab (0.25 mg/kg bolus plus infusion of 0.125 μg/kg/min for 12 h) was intravenously administered in all patients undergoing primary PCI, whereas in those with failed thrombolysis, abciximab use was left to the operator’s discretion. |
Shehata 2014 [25] | Aspirin (a loading dose of 500 mg), heparin (70 IU/kg), and clopidogrel (a loading dose of 600 mg). All patients also received the glycoprotein IIb/IIIa inhibitor abciximab with an intravenous procedural bolus of 0.25 mg/kg followed by a continuous intravenous infusion of 0.125 g/kg/min for 12 hours and postprocedural infusion without heparin. |
Sim 2013 [42] | Aspirin 300 mg, clopidogrel 600 mg, intravenous unfractionated heparin and nitroglycerin. Oral atenolol 50–100 mg was given to optimize heart rate ≤ 65 beats per minute prior to CT scan, unless contraindicated. |
Aspirin (a loading dose of 500 mg), heparin (5000 IU), and clopidogrel (a loading dose of 600 mg). Patients also received the glycoprotein IIb/IIIa inhibitor abciximab, with the dose based on body weight, unless contra-indicated, and additional heparin, with the dose based on the activated clotting time. | |
Patients received the following procedure-related medication: bivalirudin, clopidogrel or ticlopidine, acetylsalicylic acid, ticagrelor, prasugrel, heparin, low-molecular-weight heparin, and glycoprotein IIb/IIIa blocker. The use of platelet inhibitors or anticoagulants was left to the discretion of the treating physician. | |
TOTAL [6] | Unfractionated heparin; bivalirudin; enoxaparin and; glycoprotein IIb/IIa inhibitor. |
Heparin in ambulance. | |
VAMPIRE [47] | Aspirin and intravenous heparin boluses were administered during the procedure to maintain an activated clotting time ≥ 300 s. |
Yin 2011 [48] | Aspirin 300 mg and clopidogrel 300 mg prior to angiography. |
Risk of bias assessment
Author, year | Randomization sequence adequately generated? | Allocation adequately concealed? | Blinding of patients and caregivers? | Blinding of data collectors? | Blinding of adjudicators of outcome? | Blinding of data analysts? | Infrequent missing outcome data?a | Free of suggestion of selective outcome reporting? | Free of other problems that could put it at a risk of bias? |
---|---|---|---|---|---|---|---|---|---|
ADMIT (28) | Yes | Yes | No | Probably no | Probably yes | Probably no | Yes | Yes | Yes |
Bulum 2012 (29) | Probably no | Probably no | No | No | No | No | Yes | Yes | Yes |
Chao 2008 (30) | Probably yes | Probably no | No | No | No | No | Yes | Probably yes | Yes |
De Luca 2006 (31) | Probably no | Probably no | No | Probably no | Probably no | Probably no | No | Yes | Yes |
Probably yes | Probably no | No | No | Yes | No | Probably yes | Probably yes | Probably yes | |
EXPORT (34) | Yes | Yes | No | No | Yes | No | Yes | Probably no | Probably yes |
IMPACT (35) | Probably no | Probably no | No | Probably no | Probably no | Probably no | No | No | Yes |
Yes | Probably no | No | Probably no | Yes | Probably no | Yes | Yes | No | |
ITTI (38) | Yes | Probably no | No | Probably no | Probably yes | Probably no | Yes | Yes | Yes |
Kaltoft 2006 (39) | Yes | Yes | No | Probably no | Probably no | Probably no | Yes | Yes | Yes |
Liistro 2009 (40) | Yes | Probably no | No | No | Probably yes | No | Probably yes | Yes | Yes |
REMEDIA (41) | Yes | Probably yes | No | No | No | No | Probably yes | Yes | Probably yes |
Shehata 2014 (25) | Yes | Yes | No | Probably no | Yes | Probably no | Yes | Yes | Yes |
Sim 2013 (42) | Probably no | Probably no | No | No | No | No | Yes | Probably no | Yes |
Yes | Probably yes | No | No | Yes | No | Yes | Yes | Yes | |
Yes | Yes | No | No | No | Probably no | Yes | Yes | Yes | |
TOTAL (6) | Yes | Yes | No | Probably no | Yes | Probably yes | Yes | Yes | Probably no |
Yes | Yes | No | No | Yes | Probably no | Yes | Yes | Yes | |
VAMPIRE (47) | Probably yes | Probably no | No | No | Yes | No | No | Yes | Probably yes |
Yin 2011 (48) | No | No | No | No | No | No | No | No | Probably no |
Outcomes
Overall mortality
Quality assessment | Summary of findings | Certainty in estimates | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Study event rates | Relative risk (95 % CI) | Anticipated absolute effects over6 months | OR Quality of evidence | ||||||||
No of participants(studies) Range follow-up time | Risk of bias | Inconsistency | Indirectness | Imprecision | Publication bias | Without AT | With AT | Without AT | With AT | ||
Overall mortality (Includes cardiovascular (CV) mortality for studies only reporting CV mortality) | |||||||||||
20866 (20) 6–12 mo | No serious limitations1 | No serious limitations | No serious limitations2 | Serious imprecision1,3 | Undetected | 457/ 10433 | 403/ 10433 | 0.89 (0.78-1.01) | 35 per 10004 | 4 fewer per 1000 (8 fewer to 0 more) | ⊕⊕⊕⊕O MODERATE, due to imprecision |
Recurrent myocardial infarction | |||||||||||
20662 (17) 6–12 mo | No serious limitations 1 | No serious limitations | No serious limitations | Serious imprecision1,5 | Undetected | 246/ 10331 (2.3 %) | 229/10331(2.2 %) | 0.94 (0.79-1.12) | 18 per 10004 | 1 fewer per 1000 (4 fewer to 2 more) | ⊕⊕⊕⊕O MODERATE, due to imprecision |
Stroke | |||||||||||
18348 (8) 6–12 mo | No serious limitations 1 | No serious limitations | No serious limitations | Serious imprecision1,6 | Undetected | 48/ 9163 (0.5 %) | 77/9185 (0.8 %) | 1.56 (1.09-2.24) | 5 per 10004 | 3 more per 1000 (0 more to 6 more) | ⊕⊕⊕⊕O MODERATE, due to imprecision |
Major bleeding | |||||||||||
11655 (4) 6–12 mo | No serious limitations 1 | No serious limitations | No serious limitations | Serious imprecision1,5 | Undetected | 99/5823 (1.7 %) | 101/5832 (1.7 %) | 1.02 (0.78-1.35) | 15 per 10004 | 0 more per 1000 (3 fewer to 5 more) | ⊕⊕⊕⊕O MODERATE, due to imprecision |