Robert C. Welsh

Fibrinolysis or Primary PCI in ST-Segment Elevation Myocardial Infarction

BACKGROUND It is not known whether prehospital fibrinolysis, coupled with timely coronary angiography, provides a clinical outcome similar to that with primary percutaneous coronary intervention (PCI) early after acute ST-segment elevation myocardial infarction (STEMI). METHODS Among 1892 patients with STEMI who presented within 3 hours after symptom onset and who were unable to undergo primary PCI within 1 hour, patients were randomly assigned to undergo either primary PCI or fibrinolytic therapy with bolus tenecteplase (amended to half dose in patients ≥75 years of age), clopidogrel, and enoxaparin before transport to a PCI-capable hospital. Emergency coronary angiography was performed if fibrinolysis failed; otherwise, angiography was performed 6 to 24 hours after randomization. The primary end point was a composite of death, shock, congestive heart failure, or reinfarction up to 30 days. RESULTS The primary end point occurred in 116 of 939 patients (12.4%) in the fibrinolysis group and in 135 of 943 patients (14.3%) in the primary PCI group (relative risk in the fibrinolysis group, 0.86; 95% confidence interval, 0.68 to 1.09; P=0.21). Emergency angiography was required in 36.3% of patients in the fibrinolysis group, whereas the remainder of patients underwent angiography at a median of 17 hours after randomization. More intracranial hemorrhages occurred in the fibrinolysis group than in the primary PCI group (1.0% vs. 0.2%, P=0.04; after protocol amendment, 0.5% vs. 0.3%, P=0.45). The rates of nonintracranial bleeding were similar in the two groups. CONCLUSIONS Prehospital fibrinolysis with timely coronary angiography resulted in effective reperfusion in patients with early STEMI who could not undergo primary PCI within 1 hour after the first medical contact. However, fibrinolysis was associated with a slightly increased risk of intracranial bleeding. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00623623.).

Declining In-Hospital Mortality and Increasing Heart Failure Incidence in Elderly Patients With First Myocardial Infarction

OBJECTIVES The purpose of this study was to examine the long-term incidence of heart failure (HF) in elderly patients with myocardial infarction (MI). BACKGROUND In-hospital HF is common after MI and is associated with poor short-term prognosis. Limited data exist concerning the long-term incidence or prognosis of HF after MI, particularly in the era of coronary revascularization. METHODS A population-based cohort of 7,733 patients > or = 65 years of age hospitalized for a first MI (International Classification of Diseases-9th Revision-Clinical Modification code 410.x) and without a prior history of HF was established between 1994 and 2000 in Alberta, Canada, and followed up for 5 years. RESULTS During the index MI hospitalization, 2,831 (37%) MI patients were diagnosed with new HF and 1,024 (13%) died. Among hospital survivors who did not have HF during their index hospitalization (n = 4,291), an additional 3,040 patients (71%) developed HF by 5 years, 64% of which occurred in the first year. In total, 5,871 (76%) elderly patients who survived their first MI developed HF over 5 years. Among those who survived the index hospitalization, the 5-year mortality rate was 39.1% for those with HF during the index MI hospitalization compared with 26.7% among those without HF (p < 0.0001) during the index MI hospitalization. Over the study period, the 5-year mortality rate after MI decreased by 28%, whereas the 5-year rate of HF increased by 25%. CONCLUSIONS In this large cohort of elderly patients without a history of HF, HF developed in three-quarters in the 5 years after their first MI; this proportion increased over time as peri-MI mortality rates declined. New-onset HF significantly increases the mortality risk among these patients.

Intra‐pulmonary shunt and pulmonary gas exchange during exercise in humans

In young, healthy people the alveolar–arterial P  O 2 difference (A‐aDO2) is small at rest, but frequently increases during exercise. Previously, investigators have focused on ventilation/perfusion mismatch and diffusion abnormalities to explain the impairment in gas exchange, as significant physiological intra‐pulmonary shunt has not been found. The aim of this study was to use a non‐gas exchange method to determine if anatomical intra‐pulmonary (I‐P) shunts develop during exercise, and, if so, whether there is a relationship between shunt and increased A‐aDO2. Healthy male participants performed graded upright cycling to 90% while pulmonary arterial (PAP) and pulmonary artery wedge pressures were measured. Blood samples were obtained from the radial artery, cardiac output was calculated by the direct Fick method and I‐P shunt was determined by administering agitated saline during continuous 2‐D echocardiography. A‐aDO2 progressively increased with exercise and was related to (r= 0.86) and PAP (r= 0.75). No evidence of I‐P shunt was found at rest in the upright position; however, 7 of 8 subjects developed I‐P shunts during exercise. In these subjects, point bi‐serial correlations indicated that I‐P shunts were related to the increased A‐aDO2 (r= 0.68), (r= 0.76) and PAP (r= 0.73). During exercise, intra‐pulmonary shunt always occurred when A‐aDO2 exceeded 12 mmHg and was greater than 24 l min−1. These results indicate that anatomical I‐P shunts develop during exercise and we suggest that shunt recruitment may contribute to the widened A‐aDO2 during exercise.

Complete vs culprit-only revascularization for patients with multivessel disease undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a systematic review and meta-analysis.

BACKGROUND Patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease who undergo primary percutaneous coronary intervention (PCI) are most commonly treated with PCI to the culprit lesion only. Whether a strategy of complete revascularization in these patients is superior is unknown. We performed a meta-analysis comparing the benefits and risks of routine culprit-only PCI vs multivessel PCI in STEMI. METHODS MEDLINE, EMBASE, ISI Web of Science, and The Cochrane Register of Controlled Trials were searched from 1996 to January 2011. Relevant conference abstracts were searched from January 2002 to January 2011. Studies included STEMI with multivessel disease receiving primary PCI. The primary end point was long-term mortality. Data were combined using a fixed-effects model. RESULTS Of 507 citations, 26 studies (3 randomized, 23 nonrandomized; 46,324 patients, 7886 multivessel PCI and 38,438 culprit-only PCI) were included. There was no significant difference in hospital mortality with multivessel PCI vs culprit-only PCI (odds ratio [OR] 1.11, 95% CI 0.98-1.25, P = .10 [randomized OR 0.24, 95% CI 0.06-0.91, P = .04; nonrandomized OR 1.12, 95% CI 1.00-1.27, P = .06]). However, if multivessel PCI during index catheterization was performed, hospital mortality was increased (OR 1.35, 95% CI 1.19-1.54, P < .001). When multivessel PCI was performed as a staged procedure, hospital mortality was lower (OR 0.35, 95% CI 0.21-0.59; P < .001; P interaction < .001). Reduced long-term mortality (OR 0.74, 95% CI 0.65-0.85, P < .001[randomized OR 0.61, 95% CI 0.28-1.33, P = .22; nonrandomized OR 0.75, 95% CI 0.65-0.86, P < .001]) and repeat PCI (OR 0.65; 95% 0.46-0.90, P = .01[randomized OR 0.31, 95% CI 0.17-0.57, P < .001; nonrandomized OR 0.88, 95% CI 0.59-1.31, P = .54]) were observed with multivessel PCI. CONCLUSION Overall, staged multivessel PCI improved short- and long-term survival and reduced repeat PCI. Still, large randomized trials are required to confirm the benefits of staged multivessel PCI in STEMI.

Transcatheter Aortic Valve Implantation: A Canadian Cardiovascular Society Position Statement

Patients with severe symptomatic aortic stenosis have a poor prognosis with medical management alone, and balloon aortic valvuloplasty has failed to provide durable clinical benefit. Open surgical replacement of the aortic valve can improve symptoms and survival. Recently, transcatheter aortic valve implantation (TAVI) has been demonstrated to improve survival, quality of life, and functional status in nonoperable patients and to be a viable option for patients in whom the risk of open surgical morbidity or mortality is high. This Canadian Cardiovascular Society position statement represents the consensus of a representative group of cardiologists and cardiac surgeons as to the current, but evolving, role of this less-invasive new therapy. Specific recommendations are provided for selection of patients for TAVI vs surgical aortic valve replacement for native valves and for bioprostheses, approaches to patient evaluation for TAVI, appropriate constitution of multidisciplinary teams involved in performing TAVI, essential facilities that are needed to perform TAVI safely and effectively, and training/qualifications for TAVI operators. Cost considerations, complication rates, and the quality of the available evidence are also discussed. It is hoped that this consensus document will prove to be a useful resource for health professionals, institutions, departments, and decision-making bodies dealing with this important and rapidly evolving therapy.

Validation of the Global Registry of Acute Coronary Event (GRACE) risk score for in-hospital mortality in patients with acute coronary syndrome in Canada

BACKGROUND The Global Registry of Acute Coronary Event (GRACE) risk score was developed in a large multinational registry to predict in-hospital mortality across the broad spectrum of acute coronary syndromes (ACS). Because of the substantial regional variation and temporal changes in patient characteristics and management patterns, we sought to validate this risk score in a contemporary Canadian population with ACS. METHODS The main GRACE and GRACE(2) registries are prospective, multicenter, observational studies of patients with ACS (June 1999 to December 2007). For each patient, we calculated the GRACE risk score and evaluated its discrimination and calibration by the c statistic and the Hosmer-Lemeshow goodness-of-fit test, respectively. To assess the impact of temporal changes in management on the GRACE risk score performance, we evaluated its discrimination and calibration after stratifying the study population into prespecified subgroups according to enrollment period, type of ACS, and whether the patient underwent coronary angiography or revascularization during index hospitalization. RESULTS A total of 12,242 Canadian patients with ACS were included; the median GRACE risk score was 127 (25th and 75th percentiles were 103 and 157, respectively). Overall, the GRACE risk score demonstrated excellent discrimination (c statistic 0.84, 95% CI 0.82-0.86, P < .001) for in-hospital mortality. Similar results were seen in all the subgroups (all c statistics >/=0.8). However, calibration was suboptimal overall (Hosmer-Lemeshow P = .06) and in various subgroups. CONCLUSIONS GRACE risk score is a valid and powerful predictor of adverse outcomes across the wide range of Canadian patients with ACS. Its excellent discrimination is maintained despite advances in management over time and is evident in all patient subgroups. However, the predicted probability of in-hospital mortality may require recalibration in the specific health care setting and with advancements in treatment.

The Use of Antiplatelet Therapy in the Outpatient Setting: Canadian Cardiovascular Society Guidelines

Antiplatelet agents are a cornerstone of therapy for patients with atherosclerotic vascular disease. There is presently a lack of comprehensive guidelines focusing on the use of antiplatelet drugs in patients currently manifesting or at elevated risk of cardiovascular disease. The Canadian Antiplatelet Therapy Guidelines Committee reviewed existing disease-based guidelines and subsequently published literature and used expert opinion and review to develop guidelines on the use of antiplatelet therapy in the outpatient setting. This full document has been summarized in an Executive Summary published in the Canadian Journal of Cardiology and may be found at http://www.ccs.ca/. Antiplatelet therapy appears to be generally underused, perhaps in part because of a lack of clear, evidence-based guidance. Here, we provide specific guidelines for secondary prevention in patients discharged from hospital following acute coronary syndromes, post-percutaneous coronary intervention, post-coronary artery bypass grafting, patients with a history of transient cerebral ischemic events or strokes, and patients with peripheral arterial disease. Issues related to primary prevention are also addressed, in addition to special clinical contexts such as diabetes, heart failure, chronic kidney disease, pregnancy/lactation, and perioperative management. Recommendations are provided regarding pharmacologic interactions that may occur during combination therapy with warfarin, clopidogrel and proton-pump inhibitors, or acetylsalicylic acid and nonsteroidal anti-inflammatory drugs, as well as for the management of bleeding complications.

The influence of time from symptom onset and reperfusion strategy on 1-year survival in ST-elevation myocardial infarction: a pooled analysis of an early fibrinolytic strategy versus primary percutaneous coronary intervention from CAPTIM and WEST.

BACKGROUND The CAPTIM trial suggested a survival benefit of prehospital fibrinolysis (FL) compared to primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) with a presentation delay of <2 hours. We examined the relationship between reperfusion strategy and time from symptom onset on 1-year mortality in a combined analysis of 1,168 patients with STEMI. METHODS Individual patient data from CAPTIM (n = 840, 1997-2000) and the more recent WEST trial (n = 328, 2003-2005) were pooled. RESULTS Median age was 58 years, 81% were men, and 41% had anterior myocardial infarction; 640 patients were randomized to FL versus 528 patients to PCI. Both arms received contemporary adjunctive medical therapy. Presentation delay (ie, symptom onset to randomization) was similar in FL and PCI patients (median 105 [72-158] vs 106 [74-162] minutes, P = .712). Rescue PCI after FL occurred in 26% and 27%, and 30-day PCI, in 70% and 71% in CAPTIM and WEST, respectively. Mortality was not different between FL and PCI (4.6% vs 6.5%, P = .263); however, the interaction between presentation delay and treatment was significant (P = .043). Benefit with FL was observed with time <2 hours (2.8% [FL] vs 6.9% [PCI], P = .021, hazard ratio [HR] 0.43, 95% CI 0.20-0.91), whereas beyond 2 hours, no treatment difference was observed (6.9% [FL] vs 6.0% [PCI], P = .529, HR 1.23, 95% CI 0.61-2.46). CONCLUSIONS A strategy of early FL demonstrated a reduction in 1-year mortality compared to primary PCI in early presenters. Time from symptom onset should be a key consideration when selecting reperfusion therapy for STEMI.

Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y12-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI)

Despite current dual-antiplatelet therapy with aspirin and clopidogrel, adverse clinical events continue to occur during and after percutaneous coronary intervention (PCI). The failure of clopidogrel to provide optimal protection may be related to delayed onset of action, interpatient variability in its effect, and an insufficient level of platelet inhibition. Furthermore, the irreversible binding of clopidogrel to the P2Y(12) receptor for the life span of the platelet is associated with increased bleeding risk especially during urgent or emergency surgery. Novel antiplatelet agents are required to improve management of patients undergoing PCI. Elinogrel is a potent, direct-acting (ie, non-prodrug), selective, competitive, and reversible P2Y(12) inhibitor available in both intravenous and oral formulations. The INNOVATE-PCI study is a phase 2 randomized, double-blind, clopidogrel-controlled trial to evaluate the safety, tolerability, and preliminary efficacy of this novel antiplatelet agent in patients undergoing nonurgent PCI.

Outcomes after thrombus aspiration for ST elevation myocardial infarction: 1-year follow-up of the prospective randomised TOTAL trial

BACKGROUND Two large trials have reported contradictory results at 1 year after thrombus aspiration in ST elevation myocardial infarction (STEMI). In a 1-year follow-up of the largest randomised trial of thrombus aspiration, we aimed to clarify the longer-term benefits, to help guide clinical practice. METHODS The trial of routine aspiration ThrOmbecTomy with PCI versus PCI ALone in Patients with STEMI (TOTAL) was a prospective, randomised, investigator-initiated trial of routine manual thrombectomy versus percutaneous coronary intervention (PCI) alone in 10,732 patients with STEMI. Eligible adult patients (aged ≥18 years) from 87 hospitals in 20 countries were enrolled and randomly assigned (1:1) within 12 h of symptom onset to receive routine manual thrombectomy with PCI or PCI alone. Permuted block randomisation (with variable block size) was done by a 24 h computerised central system, and was stratified by centre. Participants and investigators were not masked to treatment assignment. The trial did not show a difference at 180 days in the primary outcome of cardiovascular death, myocardial infarction, cardiogenic shock, or heart failure. However, the results showed improvements in the surrogate outcomes of ST segment resolution and distal embolisation, but whether or not this finding would translate into a longer term benefit remained unclear. In this longer-term follow-up of the TOTAL study, we report the results on the primary outcome (cardiovascular death, myocardial infarction, cardiogenic shock, or heart failure) and secondary outcomes at 1 year. Analyses of the primary outcome were by modified intention to treat and only included patients who underwent index PCI. This trial is registered with ClinicalTrials.gov, number NCT01149044. FINDINGS Between Aug 5, 2010, and July 25, 2014, 10,732 eligible patients were enrolled and randomly assigned to thrombectomy followed by PCI (n=5372) or to PCI alone (n=5360). After exclusions of patients who did not undergo PCI in each group (337 in the PCI and thrombectomy group and 331 in the PCI alone group), the final study population comprised 10,064 patients (5035 thrombectomy and 5029 PCI alone). The primary outcome at 1 year occurred in 395 (8%) of 5035 patients in the thrombectomy group compared with 394 (8%) of 5029 in the PCI alone group (hazard ratio [HR] 1·00 [95% CI 0·87-1·15], p=0·99). Cardiovascular death within 1 year occurred in 179 (4%) of the thrombectomy group and in 192 (4%) of 5029 in the PCI alone group (HR 0·93 [95% CI 0·76-1·14], p=0·48). The key safety outcome, stroke within 1 year, occurred in 60 patients (1·2%) in the thrombectomy group compared with 36 (0·7%) in the PCI alone group (HR 1·66 [95% CI 1·10-2·51], p=0·015). INTERPRETATION Routine thrombus aspiration during PCI for STEMI did not reduce longer-term clinical outcomes and might be associated with an increase in stroke. As a result, thrombus aspiration can no longer be recommended as a routine strategy in STEMI. FUNDING Canadian Institutes of Health Research, Canadian Network and Centre for Trials Internationally, and Medtronic Inc.