Simon Hetherington

Randomized Trial of Complete Versus Lesion-Only Revascularization in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI and Multivessel Disease: The CvLPRIT Trial

Background The optimal management of patients found to have multivessel disease while undergoing primary percutaneous coronary intervention (P-PCI) for ST-segment elevation myocardial infarction is uncertain. Objectives CvLPRIT (Complete versus Lesion-only Primary PCI trial) is a U.K. open-label randomized study comparing complete revascularization at index admission with treatment of the infarct-related artery (IRA) only. Methods After they provided verbal assent and underwent coronary angiography, 296 patients in 7 U.K. centers were randomized through an interactive voice-response program to either in-hospital complete revascularization (n = 150) or IRA-only revascularization (n = 146). Complete revascularization was performed either at the time of P-PCI or before hospital discharge. Randomization was stratified by infarct location (anterior/nonanterior) and symptom onset (≤3 h or >3 h). The primary endpoint was a composite of all-cause death, recurrent myocardial infarction (MI), heart failure, and ischemia-driven revascularization within 12 months. Results Patient groups were well matched for baseline clinical characteristics. The primary endpoint occurred in 10.0% of the complete revascularization group versus 21.2% in the IRA-only revascularization group (hazard ratio: 0.45; 95% confidence interval: 0.24 to 0.84; p = 0.009). A trend toward benefit was seen early after complete revascularization (p = 0.055 at 30 days). Although there was no significant reduction in death or MI, a nonsignificant reduction in all primary endpoint components was seen. There was no reduction in ischemic burden on myocardial perfusion scintigraphy or in the safety endpoints of major bleeding, contrast-induced nephropathy, or stroke between the groups. Conclusions In patients presenting for P-PCI with multivessel disease, index admission complete revascularization significantly lowered the rate of the composite primary endpoint at 12 months compared with treating only the IRA. In such patients, inpatient total revascularization may be considered, but larger clinical trials are required to confirm this result and specifically address whether this strategy is associated with improved survival. (Complete Versus Lesion-only Primary PCI Pilot Study [CvLPRIT]; ISRCTN70913605)

Dimorphism in the P2Y1 ADP Receptor Gene Is Associated With Increased Platelet Activation Response to ADP

Objective— The platelet ADP receptors P2Y1 and P2Y12 play a pivotal role in platelet aggregation. There is marked interindividual variation in platelet response to ADP. We studied whether genetic variants in the P2Y1 or P2Y12 genes affect platelet response to ADP. Methods and Results— The P2Y1 and P2Y12 genes were screened for polymorphisms. Associations between selected polymorphisms and the platelet response to ADP (0.1, 1.0, and 10 μmol/L), assessed by whole blood flow cytometric measurement of fibrinogen binding to activated glycoprotein IIb-IIIa, were then determined in 200 subjects. Five polymorphisms were found in the P2Y1 gene and 11 in the P2Y12 gene. All polymorphisms were silent. A P2Y1 gene dimorphism, 1622A⟩G, was associated with a significant (P=0.007) effect on platelet ADP response, with a greater response in carriers of the G allele (frequency 0.15). The effect was seen at all concentrations of ADP but greatest at 0.1 μmol/L ADP, where the response in GG homozygotes was on average 130% higher than that seen in AA homozygotes (P=0.006). Conclusions— A common genetic variant at the P2Y1 locus is associated with platelet reactivity to ADP. This genotype effect partly explains the interindividual variation in platelet response to ADP and may have clinical implications with regard to thrombotic risk.

Complete Versus Lesion-Only Primary PCI: The Randomized Cardiovascular MR CvLPRIT Substudy

Background Complete revascularization may improve outcomes compared with an infarct-related artery (IRA)-only strategy in patients being treated with primary percutaneous coronary intervention (PPCI) who have multivessel disease presenting with ST-segment elevation myocardial infarction (STEMI). However, there is concern that non-IRA PCI may cause additional non-IRA myocardial infarction (MI). Objectives This study sought to determine whether in-hospital complete revascularization was associated with increased total infarct size compared with an IRA-only strategy. Methods This multicenter prospective, randomized, open-label, blinded endpoint clinical trial evaluated STEMI patients with multivessel disease having PPCI within 12 h of symptom onset. Patients were randomized to either IRA-only PCI or complete in-hospital revascularization. Contrast-enhanced cardiovascular magnetic resonance (CMR) was performed following PPCI (median day 3) and stress CMR at 9 months. The pre-specified primary endpoint was infarct size on pre-discharge CMR. The study had 80% power to detect a 4% difference in infarct size with 100 patients per group. Results Of the 296 patients in the main trial, 205 participated in the CMR substudy, and 203 patients (98 complete revascularization and 105 IRA-only) completed the pre-discharge CMR. The groups were well-matched. Total infarct size (median, interquartile range) was similar to IRA-only revascularization: 13.5% (6.2% to 21.9%) versus complete revascularization, 12.6% (7.2% to 22.6%) of left ventricular mass, p = 0.57 (95% confidence interval for difference in geometric means 0.82 to 1.41). The complete revascularization group had an increase in non-IRA MI on the pre-discharge CMR (22 of 98 vs. 11 of 105, p = 0.02). There was no difference in total infarct size or ischemic burden between treatment groups at follow-up CMR. Conclusions Multivessel PCI in the setting of STEMI leads to a small increase in CMR-detected non-IRA MI, but total infarct size was not significantly different from an IRA-only revascularization strategy. (Complete Versus Lesion-Only Primary PCI Pilot Study [CvLPRIT]; ISRCTN70913605)

Impact of Center Experience on Patient Radiation Exposure During Transradial Coronary Angiography and Percutaneous Intervention: A Patient-Level, International, Collaborative, Multi-Center Analysis

Background The adoption of the transradial (TR) approach over the traditional transfemoral (TF) approach has been hampered by concerns of increased radiation exposure—a subject of considerable debate within the field. We performed a patient‐level, multi‐center analysis to definitively address the impact of TR access on radiation exposure. Methods and Results Overall, 10 centers were included from 6 countries—Canada (2 centers), United Kingdom (2), Germany (2), Sweden (2), Hungary (1), and The Netherlands (1). We compared the radiation exposure of TR versus TF access using measured dose‐area product (DAP). To account for local variations in equipment and exposure, standardized TR:TF DAP ratios were constructed per center with procedures separated by coronary angiography (CA) and percutaneous coronary intervention (PCI). Among 57 326 procedures, we demonstrated increased radiation exposure with the TR versus TF approach, particularly in the CA cohort across all centers (weighted‐average ratios: CA, 1.15; PCI, 1.05). However, this was mitigated by increasing TR experience in the PCI cohort across all centers (r=−0.8; P=0.005). Over time, as a center transitioned to increasing TR experience (r=0.9; P=0.001), a concomitant decrease in radiation exposure occurred (r=−0.8; P=0.006). Ultimately, when a centers balance of TR to TF procedures approaches 50%, the resultant radiation exposure was equivalent. Conclusions The TR approach is associated with a modest increase in patient radiation exposure. However, this increase is eliminated when the TR and TF approaches are used with equal frequency—a guiding principle for centers adopting the TR approach.

Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y12 Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study

Background Third‐generation P2Y12 antagonists (prasugrel and ticagrelor) are recommended in guidelines on ST‐segment elevation myocardial infarction. Mechanisms translating their more potent antiplatelet activity into improved clinical outcomes versus the second‐generation P2Y12 antagonist clopidogrel are unclear. The aim of this post hoc analysis of the Complete Versus Lesion‐Only PRImary PCI Trial‐CMR (CvLPRIT‐CMR) substudy was to assess whether prasugrel and ticagrelor were associated with reduced infarct size compared with clopidogrel in patients undergoing primary percutaneous coronary intervention. Methods and Results CvLPRIT‐CMR was a multicenter, prospective, randomized, open‐label, blinded end point trial in 203 ST‐segment elevation myocardial infarction patients with multivessel disease undergoing primary percutaneous coronary intervention with either infarct‐related artery–only or complete revascularization. P2Y12 inhibitors were administered according to local guidelines. The primary end point of infarct size on cardiovascular magnetic resonance was not significantly different between the randomized groups. P2Y12 antagonist administration was not randomized. Patients receiving clopidogrel (n=70) compared with those treated with either prasugrel or ticagrelor (n=133) were older (67.8±12 versus 61.5±10 years, P<0.001), more frequently had hypertension (49% versus 29%, P=0.007), and tended to have longer symptom‐to‐revascularization time (234 versus 177 minutes, P=0.05). Infarct size (median 16.1% [quartiles 1–3, 10.5–27.7%] versus 12.1% [quartiles 1–3, 4.8–20.7%] of left ventricular mass, P=0.013) and microvascular obstruction incidence (65.7% versus 48.9%, P=0.022) were significantly greater in patients receiving clopidogrel. Infarct size remained significantly different after adjustment for important covariates using both generalized linear models (P=0.048) and propensity score matching (P=0.025). Conclusions In this analysis of CvLPRIT‐CMR, third‐generation P2Y12 antagonists were associated with smaller infarct size and lower microvascular obstruction incidence versus the second‐generation P2Y12 antagonist clopidogrel for ST‐segment elevation myocardial infarction. Clinical Trial Registration URL: http://www.isrctn.com/ISRCTN70913605.

Reply : Complete Revascularization in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI: Is It Really What We Should Be Doing?

We read with interest the letter from Dr. Dastidar and colleagues in which they express their views and compare our report of the randomized CvLPRIT (Complete Versus Lesion-Only Primary PCI Trial) [(1)][1] with their in-house clinical experience. They suggest that the trial was not run according to

Daily remote ischaemic conditioning following acute myocardial infarction: a randomised controlled trial

Background Remote ischaemic conditioning (rIC) is a cardioprotective tool which has shown promise in preclinical and clinical trials in the context of acute ischaemia. Repeated rIC post myocardial infarction may provide additional benefits which have not previously been tested clinically. Methods The trial assessed the role of daily rIC in enhancing left ventricular ejection fraction (LVEF) recovery in patients with impaired LVEF (<45%) after ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (P-PCI). Patients were recruited from four UK hospitals and randomised to receive either 4 weeks of daily rIC or sham conditioning using the autoRIC Device (CellAegis) starting on day 3 post P-PCI. The primary endpoint was the improvement in LVEF over 4 months assessed by cardiac MRI (CMR). Seventy-three patients (38 cases, 35 controls) completed the study. Results The treatment and control groups were well matched at baseline including for mean LVEF (42.8% vs 44.3% respectively, p=0.952). There was no difference in the improvement in LVEF over 4 months between the treatment and control groups (4.8%±7.8% vs 4.6%±5.9% respectively, p=0.924). No differences were seen in the secondary outcome measures including changes in infarct size and left ventricular end-diastolic and systolic volumes, major adverse cardiac and cerebral event, mean Kansas City Cardiomyopathy Questionnaire score and change in N-terminal pro-brain natriuretic peptide levels. Conclusions Daily rIC starting on day 3 and continued for 4 weeks following successful P-PCI for STEMI did not improve LVEF as assessed by CMR after 4 months when compared with a matched control group. Trial registration number NCT0166461.

A Woman in Her Late 50s With Palpitations and Light-headedness

A white woman in her late 50s presented with palpitations, breathlessness, chest pain, and episodes of light-headedness. Her risk profile included a family history of sudden cardiac death: her cousin died unexpectedly in his mid-40s while playing football. A physical examination showed no remarkable findings. Her systolic blood pressure was 125 mm Hg, diastolic blood pressure was 70 mm Hg, and resting heart rate was 52 beats/min. Portions of her electrocardiogram (Figure 1A) and 24-hour Holter monitoring trace (Figure 1B) are shown. Echocardiographic findings included mildly impaired systolic function (left ventricular ejection fraction, 45%-50%) but were otherwise normal. Coronary angiography was performed and revealed normal coronary arteries. Video Initial electrocardiogram A

Predictive value of segmental extent of late gadolinium enhancement and peak circumferential systolic strain in predicting improvement and normalisation of dysfunctional segments post STEMI.

Background Segmental infarct transmurality on late gadolinium enhancement (LGE) acutely post ST-elevation myocardial infarction (STEMI) has been shown to predict segmental function in a few small studies. The predictive power of segmental area of enhancement (n=45) and myocardial salvage (n=34) have been analysed in one small study each. Feature Tracking (FT) quantifies strain on routinely acquired SSFP cine images. There are no published large studies assessing segmental area of enhancement or FT-derived circumferential strain (Ecc) in predicting segmental function and improvement in the short and medium term post STEMI.

19 The randomised complete vs. lesion only primary PCI trial – cardiovascular MRI substudy (CVLPRIT-CMR)

Background Multivessel disease (MVD) occurs in ~40% of STEMI. Management is controversial. PRAMI and CVLPRIT showed improved clinical outcomes with complete versus infarct-related artery (IRA)-only revascularisation at primary percutaneous coronary intervention (PPCI). However, non-IRA PCI may cause additional infarcts. We aimed to determine whether in-hospital complete revascularisation was associated with increased myocardial injury versus an IRA-only strategy. Methods Multicentre, prospective, randomised, blinded endpoint trial. STEMI patients with MVD and <12 hr symptoms were randomised to IRA-only or complete in-hospital PCI. 1.5T CMR was performed acutely (median 3 days post-PPCI) and with adenosine stress at 9 months. The primary CMR endpoint was acute infarct size on late gadolinium imaging. Myocardial salvage index (MSI) was the proportion of non-infarcted area-at-risk. n = 100 per group gave 80% power to detect ±4% infarct size. The primary clinical outcome was 12 month combined MACE (death, repeat revascularisation, heart failure, MI). Validation studies optimised infarct, area-at-risk and strain quantification. Full-width half-maximum infarct quantification was more accurate, reproducible and correlated strongest with ejection fraction (LVEF) and infarct characteristics. Otsu’s Automated Thresholding most accurately and reproducibly assessed area-at-risk. Compared with tagging, Feature Tracking strain measurement was more robust, quicker, had better interobserver variability and correlated stronger with infarct, area-at-risk and MSI. Results (summarised in Table 1) 203 patients (98 complete revascularisation, 105 IRA-only) completed acute CMR. The groups were well matched. There was no difference in infarct size, MSI, LVEF, circumferential strain or ischaemic burden between groups. Complete revascularisation patients had increased non-IRA MI at acute CMR (Figure 1). 12 month MACE was reduced in complete revascularisation patients (8.2% vs. 17.1%, p = 0.055, hazard ratio 0.43). Conclusions Complete revascularisation in STEMI with MVD leads to a small increase in CMR-detected non-IRA MI, but total infarct size and 12 month MACE are not increased. This provides further reassurance that complete revascularisation can be considered at PPCI. Abstract 19 Table 1 Baseline, angiographic and CMR characteristics Variable IRA-only revascularisation (n = 105) Complete revascularisation (n = 98) p Baseline characteristics Age (y) 64.1 ± 10.8 63.1 ± 11.3 0.53 Male sex (n,%) 83/105 (79.0) 87/98 (88.8) 0.06 Anterior infarct (n,%) 37/105 (37.2) 35/98 (35.7) 0.94 Diabetes Mellitus (n,%) 13/105 (12.4) 15/98 (15.3) 0.55 Angiographic markers TIMI pre PCI grade 0–2 (n,%) 97/105 (92.4) 89/98 (90.8) 0.69 SYNTAX score (total) 18 (14–22) 17.3 (13–23.5) 0.81 Symptom-PCI time (TTR, min) 171 (127–268) 192 (131–302) 0.20 TIMI post PCI grade 3 (n,%) 100/105 (95.2) 89/98 (90.8) 0.21 Acute CMR Time to acute CMR (d) 2.8 (1.8–3.4) 3.0 (2.0–4.3) 0.13 LV ejection fraction (%) 45.1 ± 9.5 45.9 ± 9.9 0.60 Peak LV circumferential strain (Ecc,%) −18.1 ± 6.0 -18.6 ± 6.1 0.86 Total infarct size (% LV mass) 13.5 (6.2–21.9) 12.6 (7.2–22.6) 0.57 Patients with >1 infarct 11/105 (10.5) 22/98 (22.4) 0.02 Patients >1 acute infarct 5/105 (4.8) 17/98 (17.1) 0.004 Myocardial salvage index (%) 60.5 (40.6–81.9) 58.5 (32.8–74.9) 0.14 Follow-up CMR Time to follow-up CMR (CMR2, mth) 9.3 (8.9–9.9) 9.4 (9.0–10) 0.20 LV ejection fraction (%) 50.8 ± 8.7 49.7 ± 9.4 0.42 Peak LV circumferential strain (Ecc,%) −23.6 ± 6.3 −22.5 ± 6.3 0.28 Total infarct size (% LV mass) 7.6 (3.2–15.1) 7.3 (3.0–14.4) 0.41 Patients with >1 infarct (%) 9/80 (11.2) 20/84 (23.8) 0.035 Presence of ischaemia (n,%) in all pats 16/77 (20.8) 17/82 (20.7) 0.99 Global ischaemic burden (%) all pats 4.3 ± 11.3 3.4 ± 8.9 0.81 Abstract 19 Figure 1 Multiple infarcts on late gadolinium imaging in complete revascularisation patients The 2 images on left and 2 images on right are 2 different patients. A = main infarct-related artery territory infarct B = infarct in non-infarct related artery territory