Characteristics and Outcomes of Patients With ST-Segment Elevation Myocardial Infarction Excluded from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial
2012; Elsevier BV; Volume: 111; Issue: 2 Linguagem: Inglês
10.1016/j.amjcard.2012.09.019
ISSN1879-1913
AutoresLuigi Fiocca, Giulio Guagliumi, Roberta Rossini, Helen Parise, Giuseppe Musumeci, Vasile Sirbu, Nikoloz Lortkipanidze, Jennifer Yu, Laurian Mihalcsik, Angelina Vassileva, Orazio Valsecchi, Antonello Gavazzi, Roxana Mehran, Gregg W. Stone,
Tópico(s)Cardiac Imaging and Diagnostics
ResumoRandomized controlled trials assessing new drugs and devices tend to exclude subjects who are at greatest risk. The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial incorporated broader inclusion criteria in an attempt to include a more representative spectrum of patients presenting with ST-segment elevation myocardial infarction (STEMI). To identify the differences between this modern trial and the real world, we analyzed the characteristics and outcomes of patients with STEMI who were screened but not enrolled at a high-volume recruiting center. Of 318 consecutive patients with STEMI who were screened, 200 (62.9%) were randomized, and 118 (37.1%) were excluded. The baseline characteristics and 30-day and 1-year clinical outcomes were compared in the 2 groups. The excluded patients had numerous high-risk features compared to those randomized, including being older (67.0 ± 12.8 vs 63.0 ± 11.4 years, p = 0.004), more often had had a previous MI (34.7% vs 8.0%, p <0.001), Killip class III-IV (27.4% vs 4.0%, p <0.001), and lower hemoglobin (13.4 ± 2.3 vs 14.8 ± 1.5 g/dl, p <0.001). The excluded patients had markedly greater 30-day and 1-year rates of all-cause mortality (17.4% vs 2.0%, p <0.001, and 27.6% vs 2.5%, p <0.001, respectively), major adverse cardiovascular events (death, MI, ischemia-driven target vessel revascularization, and stroke), major bleeding, and net adverse clinical events (major adverse cardiovascular events or major bleeding). On multivariate analysis, Killip class III-IV at presentation, age, left ventricular ejection fraction, and final Thrombolysis In Myocardial Infarction flow grade 3 were independent predictors of outcome. In conclusion, despite the broadened entry criteria of the HORIZONS-AMI trial, 37.1% of all patients presenting with STEMI at a center with a high rate of enrollment were judged to be ineligible and were excluded. The excluded patients had a significantly greater risk profile and markedly increased mortality and adverse events compared to the trial-eligible group. Randomized controlled trials assessing new drugs and devices tend to exclude subjects who are at greatest risk. The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial incorporated broader inclusion criteria in an attempt to include a more representative spectrum of patients presenting with ST-segment elevation myocardial infarction (STEMI). To identify the differences between this modern trial and the real world, we analyzed the characteristics and outcomes of patients with STEMI who were screened but not enrolled at a high-volume recruiting center. Of 318 consecutive patients with STEMI who were screened, 200 (62.9%) were randomized, and 118 (37.1%) were excluded. The baseline characteristics and 30-day and 1-year clinical outcomes were compared in the 2 groups. The excluded patients had numerous high-risk features compared to those randomized, including being older (67.0 ± 12.8 vs 63.0 ± 11.4 years, p = 0.004), more often had had a previous MI (34.7% vs 8.0%, p <0.001), Killip class III-IV (27.4% vs 4.0%, p <0.001), and lower hemoglobin (13.4 ± 2.3 vs 14.8 ± 1.5 g/dl, p <0.001). The excluded patients had markedly greater 30-day and 1-year rates of all-cause mortality (17.4% vs 2.0%, p <0.001, and 27.6% vs 2.5%, p <0.001, respectively), major adverse cardiovascular events (death, MI, ischemia-driven target vessel revascularization, and stroke), major bleeding, and net adverse clinical events (major adverse cardiovascular events or major bleeding). On multivariate analysis, Killip class III-IV at presentation, age, left ventricular ejection fraction, and final Thrombolysis In Myocardial Infarction flow grade 3 were independent predictors of outcome. In conclusion, despite the broadened entry criteria of the HORIZONS-AMI trial, 37.1% of all patients presenting with STEMI at a center with a high rate of enrollment were judged to be ineligible and were excluded. The excluded patients had a significantly greater risk profile and markedly increased mortality and adverse events compared to the trial-eligible group. The treatment recommendations for treating patients with acute ST-segment elevation myocardial infarction (STEMI) rely heavily on the results of randomized controlled trials (RCTs).1Van de Werf F. Bax J. Betriu A. Blomstrom-Lundqvist C. Crea F. Falk V. Filippatos G. Fox K. Huber K. Kastrati A. Rosengren A. Steg P.G. Tubaro M. Verheugt F. Weidinger F. Weis M. ESC Committee for Practice Guidelines (CPG)Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-segment Elevation Acute Myocardial Infarction of the European Society of Cardiology.Eur Heart J. 2008; 29: 2909-2945Crossref PubMed Scopus (1) Google Scholar However, RCTs of primary percutaneous coronary intervention (PCI) in STEMI often recruit relatively low-risk patients, making it difficult to generalize the results to a “real-world” population.2Steg P.G. López-Sendón J. Lopez de Sa E. Goodman S.G. Gore J.M. Anderson Jr., F.A. Himbert D. Allegrone J. Van de Werf F. GRACE InvestigatorsExternal validity of clinical trials in acute myocardial infarction.Arch Intern Med. 2007; 167: 68-73Crossref PubMed Scopus (237) Google Scholar, 3Rothwell P.M. External validity of randomised controlled trials: “to whom do the results of this trial apply?”.Lancet. 2005; 365: 82-93Abstract Full Text Full Text PDF PubMed Scopus (1808) Google Scholar The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial was designed to allow enrollment of a broader cross-section of patients than included in earlier RCTs.4Stone G.W. Witzenbichler B. Guagliumi G. Peruga J.Z. Brodie B.R. Dudek D. Kornowski R. Hartmann F. Gersh B.J. Pocock S.J. Dangas G. Wong S.C. Kirtane A.J. Parise H. Mehran R. HORIZONS-AMI Trial InvestigatorsBivalirudin during primary PCI in acute myocardial infarction.N Engl J Med. 2008; 358: 2218-2230Crossref PubMed Scopus (1626) Google Scholar In brief, in the HORIZONS-AMI trial, 3,602 patients with STEMI symptom onset within 12 hours were randomized to either unfractionated heparin plus the routine use of a glycoprotein IIb/IIIa inhibitor or bivalirudin monotherapy. After angiography, eligible patients underwent a second randomization (3:1) to either paclitaxel-eluting stents or bare metal stents. Patients of any age, including those with cardiogenic shock at admission, previous cardiac arrest, renal insufficiency, multivessel disease, and protected left main or saphenous vein graft infarct lesions were eligible. The principal results of the HORIZONS-AMI trial have been previously reported.4Stone G.W. Witzenbichler B. Guagliumi G. Peruga J.Z. Brodie B.R. Dudek D. Kornowski R. Hartmann F. Gersh B.J. Pocock S.J. Dangas G. Wong S.C. Kirtane A.J. Parise H. Mehran R. HORIZONS-AMI Trial InvestigatorsBivalirudin during primary PCI in acute myocardial infarction.N Engl J Med. 2008; 358: 2218-2230Crossref PubMed Scopus (1626) Google Scholar, 5Stone G.W. Lansky A.J. Pocock S.J. Gersh B.J. Dangas G. Wong S.C. Witzenbichler B. Guagliumi G. Peruga J.Z. Brodie B.R. Dudek D. Möckel M. Ochala A. Kellock A. Parise H. Mehran R. HORIZONS-AMI Trial InvestigatorsPaclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction.N Engl J Med. 2009; 360: 1946-1959Crossref PubMed Scopus (403) Google Scholar, 6Stone G.W. Witzenbichler B. Guagliumi G. Peruga J.Z. Brodie B.R. Dudek D. Kornowski R. Hartmann F. Gersh B.J. Pocock S.J. Dangas G. Wong S.C. Fahy M. Parise H. Mehran R. HORIZONS-AMI Trial InvestigatorsHeparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial.Lancet. 2011; 377: 2193-2204Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar A screening log of excluded patients was not routinely maintained at all sites. To analyze the differences between the trial and the real world, we examined the baseline clinical and angiographic characteristics and long-term outcomes of patients screened but excluded from the HORIZONS-AMI trial at a single, high-volume, recruiting center. The present study was conducted at Ospedali Riuniti di Bergamo (Bergamo, Italy), the second greatest recruiting center in the HORIZONS-AMI trial. Patient eligibility was sequentially determined for all consecutive patients with STEMI and an indication for primary PCI, who presented at our center during the trial recruitment period (August 10, 2005 to May 7, 2007). The exclusion criteria have been previously reported.4Stone G.W. Witzenbichler B. Guagliumi G. Peruga J.Z. Brodie B.R. Dudek D. Kornowski R. Hartmann F. Gersh B.J. Pocock S.J. Dangas G. Wong S.C. Kirtane A.J. Parise H. Mehran R. HORIZONS-AMI Trial InvestigatorsBivalirudin during primary PCI in acute myocardial infarction.N Engl J Med. 2008; 358: 2218-2230Crossref PubMed Scopus (1626) Google Scholar In brief, because the trial tested an anticoagulant drug (bivalirudin), the clinical conditions determining an increased bleeding risk were considered as the main exclusion criteria. Noncardiac coexisting conditions that could limit life expectancy to <1 year or that might interfere with protocol compliance and an inability to obtain written informed consent were also considered as exclusion criteria. Patients who did not meet any of the entry criteria for randomization but otherwise had indications for primary PCI were included in the present study as the “trial-ineligible” group. Informed consent for primary PCI was obtained from each patient or patient representative, when needed. Drug and device usage for randomized patients enrolled in the HORIZONS-AMI trial have been previously reported in detail.4Stone G.W. Witzenbichler B. Guagliumi G. Peruga J.Z. Brodie B.R. Dudek D. Kornowski R. Hartmann F. Gersh B.J. Pocock S.J. Dangas G. Wong S.C. Kirtane A.J. Parise H. Mehran R. HORIZONS-AMI Trial InvestigatorsBivalirudin during primary PCI in acute myocardial infarction.N Engl J Med. 2008; 358: 2218-2230Crossref PubMed Scopus (1626) Google Scholar All excluded patients were treated with 250 mg intravenous aspirin and an intravenous bolus (70 U/kg) of unfractionated heparin before cardiac catheterization. During PCI, additional heparin boluses were given to maintain the activating clotting time at 250 to 300 seconds. The activating clotting time was routinely tested during the procedure in all patients. Glycoprotein IIb/IIIa inhibitor use was at the discretion of the operator but discouraged in the case of a high risk of bleeding. A loading dose of clopidogrel 300 mg was administered immediately before PCI in all patients. PCI was performed by the femoral or radial approach, according to the physician's decision. The radial route was preferentially selected in presence of bleeding diathesis or known thrombocytopenia. Manual thrombus aspiration was used in patients with a large thrombus burden. Balloon angioplasty and stenting were performed according to standard practice. The choice to implant a bare metal stent or drug-eluting stent was left to operator discretion. After the procedure, the femoral arterial access sheath was removed when the activating clotting time was <180 seconds or immediately if the radial approach had been used. After successful PCI, all patients (enrolled and excluded) were treated with aspirin 100 mg once/day indefinitely and clopidogrel 75 mg/day for ≥6 months if a drug-eluting stent had been implanted (typically 12 months) or for ≥1 month if a bare metal stent had been used. Detailed clinical, procedural, and outcomes data for the enrolled patients were collected and entered into the electronic HORIZONS-AMI case report form. A data set with common elements was collected from the excluded patients to allow a comparison of the 2 groups. In-hospital events were tracked, and any major adverse cardiovascular events (MACE; composite of death, MI, ischemia-driven target vessel revascularization, and stroke) and major bleeding events, according to the HORIZONS-AMI definitions,4Stone G.W. Witzenbichler B. Guagliumi G. Peruga J.Z. Brodie B.R. Dudek D. Kornowski R. Hartmann F. Gersh B.J. Pocock S.J. Dangas G. Wong S.C. Kirtane A.J. Parise H. Mehran R. HORIZONS-AMI Trial InvestigatorsBivalirudin during primary PCI in acute myocardial infarction.N Engl J Med. 2008; 358: 2218-2230Crossref PubMed Scopus (1626) Google Scholar were evaluated and recorded. Patients alive at hospital discharge were followed by telephone interviews or outpatient clinical visits at 30 days, 6 months, and 1 year. We sought to determine the rates of all-cause and cardiac mortality at 30 days and 1 year. MACE, non–coronary artery bypass grafting (CABG)-related major bleeding, and net adverse clinical events (MACE and non–CABG major bleeding), according to HORIZONS-AMI protocol definitions, were assessed in the enrolled and excluded patients. Continuous variables are summarized as the mean ± SD and were compared using the t test. Categorical variables are displayed as frequencies and percentages, and the groups were compared using the chi-square test. In addition, the outcomes data for the randomized and trial-ineligible groups were plotted as time-to-event curves using Kaplan-Meier estimates and compared using the log-rank test. Hazard ratios and 95% confidence intervals from the Cox proportional hazards models are displayed. Independent predictors of 1-year mortality, MACE, non–CABG major bleeding, and net adverse clinical events were evaluated using Cox proportional hazards regression analysis. Additional covariates known to affect the outcomes in STEMI were entered into the model in a stepwise fashion, including age, left ventricular ejection fraction, diabetes, Killip class, renal insufficiency, use of bivalirudin, and final Thrombolysis In Myocardial Infarction 3 flow (vs 0–2 flow). Variables that were significant at the 0.05 level were kept in the model. All analyses were 2-sided, and p <0.05 defined statistical significance. A total of 318 patients were screened for enrollment. Of these, 200 (62.9%) were enrolled and randomized in the HORIZONS-AMI trial and 118 (37.1%) were considered trial ineligible for specific reasons (Table 1). The most common reasons for trial ineligibility were increased bleeding risk, intubation after cardiac arrest, and extreme hemodynamic instability. Other common reasons included ST-segment resolution on the qualifying electrocardiogram (despite earlier definite ST-segment elevation), and suspected stent thrombosis. The reason for trial exclusion was unclear in 7 patients (5.9%), and in 14 patients (11.9%), multiple exclusion criteria were present.Table 1Reasons for exclusion from randomization (n = 118)Exclusion Criterian (%)Increased bleeding risk28 (23.7)Intubation after cardiac arrest or severe hemodynamic instability26 (22.0)ST-segment resolution on baseline electrocardiogram16 (13.6)Suspected stent thrombosis12 (10.2)Allergy to study medications8 (6.8)Life expectancy 12 h)4 (3.4)Cognitive impairment4 (3.4)Consent refused7 (5.9)Enrolled in another trial3 (2.5)Psychiatric illness (unlikely to comply with study procedures)2 (1.7)Human immunodeficiency virus infection1 (0.8)Undetermined reasons for exclusion7 (5.9)Multiple reasons for exclusion14 (11.9) Open table in a new tab The baseline characteristics of the 2 groups are listed in Table 2. Compared to the enrolled patients, those excluded were older, more frequently had diabetes, renal insufficiency (creatinine clearance 3 days longer in the trial-ineligible patients (10.5 ± 14.3 vs 7.0 ± 6.0 days, p = 0.004), mainly because of the critical conditions at presentation of many of the excluded patients, such as those with cardiac arrest and Killip class III or IV. Follow-up data of the excluded patients were available for 100% at 30 days and 97.5% at 1 year. The excluded patients had markedly greater mortality at 30 days and 1 year compared to those randomized (Table 4 and Figure 1). The 30-day and 1-year mortality were significantly greater for the excluded patients presenting in Killip class I or II (7.8% vs 1.0%, p <0.001, and 15.6% vs 1.0%, p <0.001, respectively). Similar trends (which did not reach statistical significance) were observed in patients presenting in Killip class III or IV (46.4% vs 25.0%, p = 0.42, and 64.3% vs 37.5%, p = 0.24, respectively). The 30-day and 1-year rates of cardiac death, MACE, non–CABG major bleeding, and net adverse clinical events were also substantially greater in the patients ineligible for trial randomization (Table 4 and Figure 1). Noncardiac death did not occur during follow-up among the 6 patients excluded because of a life expectancy of 75 yrs31 (15.5%)39 (33.1%) 240 mg/dl and/or low-density lipoprotein >130 mg/dl, and/or triglycerides >150 mg/dl (National Cholesterol Education Program Adult Treatment Panel III classification).95 (47.5%)51 (43.2%)0.46Hypertension87 (43.5%)62 (52.5%)0.12Smoker119 (59.5%)51 (43.2%)0.005Renal failure†Defined as creatinine clearance of <60 ml/min as calculated using Cockcroft–Gault equation.2 (1%)21 (17.8%)<0.001Previous myocardial infarction16 (8%)41 (34.7%)<0.001Previous percutaneous coronary intervention17 (8.5%)29 (24.6%)0.002Previous coronary artery bypass grafting3 (1.5%)9 (7.6%)0.001Killip class III or IV8 (4.0%)28 (23.7%)<0.001 III3 (1.5%)7 (5.9%)0.043 IV5 (2.5%)21 (17.8%)<0.001Left ventricular ejection fraction (%)52.2 ± 7.144.1 ± 12.4<0.001Heart rate (beats/min)78 ± 1785 ± 240.006Hemoglobin (g/dl)14.8 ± 1.513.4 ± 2.3 240 mg/dl and/or low-density lipoprotein >130 mg/dl, and/or triglycerides >150 mg/dl (National Cholesterol Education Program Adult Treatment Panel III classification).† Defined as creatinine clearance of <60 ml/min as calculated using Cockcroft–Gault equation. Open table in a new tab Table 3Procedural and angiographic characteristicsVariableEnrolled and Randomized (n = 200)Excluded (n = 118)p ValueRadial arterial access35 (17.5%)31 (26.3%)<0.001Baseline Thrombolysis In Myocardial Infarction flow grade 0–1139 (72.8%)84 (71.2%)0.76Final Thrombolysis In Myocardial Infarction flow grade 3184 (92%)105 (89.0%)0.37Infarct-related artery Left main artery4 (2.1%)5 (4.2%)0.27 Left anterior descending artery96 (48%)55 (46.6%)0.81 Left circumflex artery32 (16%)21 (17,8%)0.68 Right artery72 (36%)40 (33,9%)0.71 Saphenous vein graft2 (1.0%)3 (2.5%)0.31Procedural anticoagulation Unfractionated heparin100 (50.0%)118 (100%)<0.001 Bivalirudin100 (50.0%)0 (0%)<0.001Glycoprotein IIb/IIIa inhibitor used107 (53.5%)29 (24.6%)<0.001Interval from symptom onset to balloon inflation (h)4.5 ± 2.53.9 ± 2.60.03≥1 Stents implanted184 (92.0%)105 (89.0%)0.37 Any bare metal stent implanted52 (28.6%)76 (64.4%)<0.001 Any drug-eluting stent implanted134 (73.6%)29 (24.6%)<0.001Thrombus aspiration27 (14.4%)19 (16.1%)0.68Intra-aortic balloon counterpulsation7 (3.5%)23 (19.5%)<0.001 Open table in a new tab Table 4Outcomes at 30 days and 1 year30-Day Outcomes1-Year OutcomesEnrolled and Randomized (n = 200)Excluded (n = 118)p ValueEnrolled and Randomized (n = 200)Excluded (n = 115)p ValueAll-cause death4 (2.0%)20 (17.1%)<0.0015 (2.5%)32 (27.6%)<0.001Cardiac death4 (2.0%)20 (17.1%)<0.0015 (2.5%)26 (22.0%)<0.001Reinfarction3 (1.5%)2 (1.9%)0.819 (4.6%)5 (5.7%)0.79Ischemia-driven target vessel revascularization2 (1.0%)1 (1.0%)0.9610 (5.2%)5 (5.7%)0.88Major adverse cardiovascular events7 (3.5%)22 (18.8%)<0.00120 (10.0%)42 (36.6%)<0.001Major bleeding (noncoronary artery bypass grafting)25 (12.5%)30 (25.4%)0.00325 (12.6%)30 (26.1%)0.003Net adverse clinical events30 (15.0%)42 (35.6%)<0.00139 (19.6%)49 (41.7%)<0.001 Open table in a new tab Table 5Independent predictors of 1-year all-cause mortality, major adverse cardiovascular events (MACE), noncoronary artery bypass grafting (CABG) major bleeding, and net adverse clinical eventsHR95% CIp ValueAll-cause mortality Killip class III-IV3.121.49–6.530.002 Age1.061.02–1.090.001 Left ventricular ejection fraction0.940.91–0.97 1 decade ago, the Primary Angioplasty in Myocardial Infarction (PAMI) stent investigators reported that approximately 50% of patients at a single, high-volume center were ineligible for enrollment17Dauerman H.L. Pinto D.S. Ho K.K. Gibson C.M. Kuntz R.E. Cohen D.J. Baim D.S. Carrozza Jr., J.P. Outcome of patients with acute myocardial infarction who are ineligible for primary angioplasty trials.Catheter Cardiovasc Interv. 2000; 49: 237-243Crossref PubMed Scopus (13) Google Scholar and had a mortality rate more than fivefold greater than those meeting the trial inclusion criteria (21% vs 4%, p = 0.003). More recently, the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) investigators reported the features and outcomes of clinically eligible patients excluded from randomization because of unsuitable coronary anatomy for stenting.18Halkin A. Stone G.W. Grines C.L. Cox D.A. Stuckey T.D. Garcia E. Guagliumi G. Mehran R. Rutherford B.D. Griffin J.J. Na Y. Tcheng J.E. Turco M. Outcomes of patients consented but not randomized in a trial of primary percutaneous coronary intervention in acute myocardial infarction (the CADILLAC Registry).Am J Cardiol. 2005; 96: 1649-1655Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar The registry patients (23% of all patients who agreed) compared to those randomized were older, had a greater risk profile, and significantly greater in-hospital mortality (4.0% vs 1.6%, relative risk 2.45, p = 0.001). Steg et al2Steg P.G. López-Sendón J. Lopez de Sa E. Goodman S.G. Gore J.M. Anderson Jr., F.A. Himbert D. Allegrone J. Van de Werf F. GRACE InvestigatorsExternal validity of clinical trials in acute myocardial infarction.Arch Intern Med. 2007; 167: 68-73Crossref PubMed Scopus (237) Google Scholar divided consecutive patients with STEMI from the Global Registry of Acute Coronary Events (GRACE) into 3 groups: RCT participants, RCT-eligible but not enrolled patients, and ineligible patients. A gradient of risk was observed from the patients who were included in RCTs (lowest risk) to those ineligible (greatest risk), with a mortality rate of 3.6%, 7.1%, and 11.4% respectively (p = 0.001).2Steg P.G. López-Sendón J. Lopez de Sa E. Goodman S.G. Gore J.M. Anderson Jr., F.A. Himbert D. Allegrone J. Van de Werf F. GRACE InvestigatorsExternal validity of clinical trials in acute myocardial infarction.Arch Intern Med. 2007; 167: 68-73Crossref PubMed Scopus (237) Google Scholar Finally, similar findings were observed in >20,000 patients with STEMI from the Maximal Individual Therapy of Acute Myocardial Infarction (MITRA) Plus registry.19Koeth O. Zahn R. Gitt A.K. Bauer T. Juenger C. Senges J. Zeymer U. Maximal Individual Therapy in Acute Myocardial Infarction Plus Study GroupClinical benefit of early reperfusion therapy in patients with ST-elevation myocardial infarction usually excluded from randomized clinical trials (results from the Maximal Individual Therapy in Acute Myocardial Infarction Plus [MITRA Plus] registry).Am J Cardiol. 2009; 104: 1074-1077Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar The RCT-ineligible patients (46.4%) more often had baseline risk characteristics, less often received early reperfusion and other evidence-based therapies, and had greater in-hospital mortality (20.1% vs 4.9%, p <0.0001) compared to the eligible patients. The peculiarity of our study was that we analyzed all consecutive patients treated at a single, high-volume primary PCI center, thus reducing the heterogeneity of the treatment and selection biases typical of multicenter registries and meta-analyses. The standard of care was applied to all the excluded patients, comparing their outcomes with those from a modern trial, designed with the aim of enrolling the largest number of patients. The HORIZONS-AMI trial had fewer exclusion criteria than most other STEMI RCTs. Nonetheless, only 62.9% of consecutive patients were enrolled at a highly motivated center. The most common reason for exclusion was increased hemorrhagic risk (present in nearly 1 in 4 excluded patients), a typical contraindication to abciximab. The second most common reason for exclusion, intubation after cardiac arrest or severe hemodynamic instability, was not actually a formal trial exclusion criterion. These patients could not be enrolled, however, because of clinical care urgency, an inability to consent (guardian not present), or other reasons. Consistent with previous data, patients excluded from the HORIZONS-AMI trial had significantly worse outcomes, with markedly greater early and late rates of mortality and MACE. The rates of mortality and adverse ischemic events diverged immediately after treatment and separated further between 30 days and 1 year (Figure 1). Also of note (and not previously reported, although not unexpected) was the substantially greater rate of non–CABG-related major bleeding and net adverse clinical events in patients excluded from randomization. It is possible that the improved outcomes of patients enrolled in the trial might, in part, be attributed to the participation in a RCT, leading to closer medical attention and overall better care. In this regard, the survival benefit of bivalirudin has been attributed to its effect in preventing major bleeding,20Mehran R. Pocock S. Nikolsky E. Dangas G.D. Clayton T. Claessen B.E. Caixeta A. Feit F. Manoukian S.V. White H. Bertrand M. Ohman E.M. Parise H. Lansky A.J. Lincoff A.M. Stone G.W. Impact of bleeding on mortality after percutaneous coronary intervention results from a patient-level pooled analysis of the REPLACE-2 (Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy), and HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trials.JACC Cardiovasc Interv. 2011; 4: 654-664Crossref PubMed Scopus (333) Google Scholar and had bivalirudin (not available for sale in Italy during the study period) been used in the excluded group of patients, it might have resulted in a greater reduction in bleeding and mortality. Although the radial access approach in the group of excluded patients was about fourfold higher than that in the HORIZONS-AMI trial (26.3% vs 6%),21Généreux P. Mehran R. Palmerini T. Caixeta A. Kirtane A.J. Lansky A.J. Brodie B.R. Witzenbichler B. Mockel M. Guagliumi G. Peruga J.Z. Dudek D. Fahy M.P. Dangas G. Stone G.W. Radial access in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty in acute myocardial infarction: the HORIZONS-AMI trial.EuroIntervention. 2011; 7: 905-916Crossref PubMed Scopus (83) Google Scholar a more extensive use of the radial approach would have probably reduced the incidence of bleeding and improved the outcomes of the excluded patients. The relatively low rate of such a technique could have been related to the high incidence of Killip III and IV class and the incomplete training in the radial approach during STEMI for some operators at that time. The results from the present study have highlighted the evidence gap between RCTs and clinical practice, pointing to the need for alternative methods to evaluate the outcomes of new therapies for high-risk patients excluded from RCTs. Patients are often treated according to guidelines that have mostly been derived from RCTs that are not representative of all patients treated in clinical practice. The increasing complexity of patients undergoing interventional procedures, with older age and more frequent co-existing co-morbidities, suggests that RCTs should strive as much as possible to minimize the exclusion criteria to yield results that are generalizable. However, a recently published analysis of patient enrollment from 2 “all-comers” PCI trials, Limus Eluted From A Durable Versus ERodable Stent Coating (LEADERS) and A Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention (RESOLUTE-III), reported that only 48% of a consecutive series of patients were enrolled, with the most common exclusion criteria being an inability to provide informed consent, a refusal to participate, or the presence of 1 of the few remaining exclusion criteria.22de Boer S.P. Lenzen M.J. Oemrawsingh R.M. Simsek C. Duckers H.J. van der Giessen W.J. Serruys P.W. Boersma E. Evaluating the “all-comers” design: a comparison of participants in two “all-comers” PCI trials with non-participants.Eur Heart J. 2011; 32: 2161-2167Crossref PubMed Scopus (70) Google Scholar The 30-day mortality was markedly lower in the study participants than in the nonparticipants (0.7% vs 4.5%, adjusted hazard ratio 0.18, 95% confidence interval 0.06 to 0.52). Thus, despite their limitations,23Austin P.C. Mamdani M.M. Stukel T.A. Anderson G.M. Tu J.V. The use of the propensity score for estimating treatment effects: administrative versus clinical data.Stat Med. 2005; 24: 1563-1578Crossref PubMed Scopus (172) Google Scholar carefully conducted postmarket observational studies will continue to be essential to monitor new drug and device safety, especially when used for off-label indications. The present study had several limitations. First, the data were derived from a high-enrolling, single center, possibly underestimating the proportion excluded from randomization at other sites. However, a global screen registry was not maintained at all sites participating in the HORIZONS-AMI trial. Although the major reasons for trial ineligibility were prospectively captured on the case report form, other reasons might have been present that were not collected, such as patient frailty, lack of social support, and so forth. Finally, as a post hoc analysis, the present study should be considered exploratory and hypothesis-generating. Dr. Guagliumi reports receiving consulting fees from Boston Scientific, St. Jude Medical, Volcano, Cordis and receiving grant support from Abbott Vascular, LigthLab Imaging, Medtronic Vascular, and Boston Scientific. Dr. Mehran reports consulting fees from Astra Zeneca, on the scientific advisory boards for Johnson&Johnson and Regado Biosciences and receiving research grant support (institutional) from BMS/Sanofi and the Medicines Co. Dr. Stone serves reports consulting fees from Abbott Vascular and Boston Scientific, Medtronic and Medicines Co. Drs. Fiocca, Musumeci, Rossini, Sirbu, Lortkipanidze, Vassileva, Valsecchi, Parise and Yu report no conflicts.
Referência(s)