Marc J. Schweiger

TNK–Tissue Plasminogen Activator Compared With Front-Loaded Alteplase in Acute Myocardial Infarction Results of the TIMI 10B Trial

BACKGROUND Bolus thrombolytic therapy is a simplified means of administering thrombolysis that facilitates rapid time to treatment. TNK-tissue plasminogen activator (TNK-tPA) is a highly fibrin-specific single-bolus thrombolytic agent. METHODS AND RESULTS In TIMI 10B, 886 patients with acute ST-elevation myocardial infarction presenting within 12 hours were randomized to receive either a single bolus of 30 or 50 mg TNK-tPA or front-loaded tPA and underwent immediate coronary angiography. The 50-mg dose was discontinued early because of increased intracranial hemorrhage and was replaced by a 40-mg dose, and heparin doses were decreased. TNK-tPA 40 mg and tPA produced similar rates of TIMI grade 3 flow at 90 minutes (62.8% versus 62.7%, respectively, P=NS); the rate for the 30-mg dose was significantly lower (54.3%, P=0.035) and was 65. 8% for the 50-mg dose (P=NS). A prespecified analysis of weight-based TNK-tPA dosing using median TIMI frame count demonstrated a dose response (P=0.001). Similar dose responses were observed for serious bleeding and intracranial hemorrhage, but significantly lower rates were observed for both TNK-tPA and tPA after the heparin doses were lowered and titration of the heparin was started at 6 hours. CONCLUSIONS TNK-tPA, given as a single 40-mg bolus, achieved rates of TIMI grade 3 flow similar to those of the 90-minute bolus and infusion of tPA. Weight-adjusting TNK-tPA appears to be important in achieving optimal reperfusion; reduced heparin dosing appears to improve safety for both agents. Together with the safety results from the parallel Assessment of the Safety of a New Thrombolytic: TNK-tPA (ASSENT I) trial, an appropriate dose of this single-bolus thrombolytic agent has been identified for phase III testing.

A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial

OBJECTIVES The purpose of this study was to assess the value of recombinant desulfatohirudin (hirudin) as adjunctive therapy to thrombolysis in acute myocardial infarction. BACKGROUND Failure to achieve initial reperfusion and reocclusion of the infarct-related artery remain major limitations of thrombolytic therapy despite aggressive regimens of heparin and aspirin. Hirudin, a direct thrombin inhibitor, has been shown in experimental models to enhance thrombolysis and reduce reocclusion. METHODS The Thrombolysis in Myocardial Infarction (TIMI) 5 trial was a randomized, dose-ranging, pilot trial of hirudin versus heparin, given with front-loaded tissue-type plasminogen activator and aspirin to 246 patients with acute myocardial infarction. Patients received either intravenous heparin or hirudin at one of four ascending doses for 5 days. Patients underwent coronary angiography at 90 min and at 18 to 36 h, unless rescue angioplasty was performed. RESULTS The primary end point, TIMI grade 3 flow in the infarct-related artery at 90 min and 18 to 36 h without death or reinfarction before the 18- to 36-h catheterization was achieved in 97 (61.8%) of 157 evaluable hirudin-treated patients compared with 39 (49.4%) of 79 evaluable heparin-treated patients (p = 0.07). All four doses of hirudin led to similar findings in the angiographic and clinical end points. At 90 min, TIMI grade 3 flow was present in 105 (64.8%) of 162 hirudin-treated patients compared with 48 (57.1%) of 84 heparin-treated patients (p = NS). Infarct-related artery patency (TIMI grade 2 or 3 flow) was similar in the two groups (82.1% and 78.6%, respectively). At 18 to 36 h, 129 (97.8%) of 132 hirudin-treated patients had a patent infarct-related artery compared with 58 (89.2%) of 65 heparin-treated patients (p = 0.01). Reocclusion by 18 to 36 h occurred in 2 (1.6%) of 123 hirudin-treated patients versus 4 (6.7%) of 60 heparin-treated patients (p = 0.07). Death or reinfarction occurred during the hospital period in 11 (6.8%) of 162 hirudin-treated patients compared with 14 (16.7%) of 84 heparin-treated patients (p = 0.02). Major spontaneous hemorrhage occurred in 1.2% of hirudin-treated patients versus 4.7% of heparin-treated patients (p = 0.09), and major hemorrhage at an instrumented site occurred in 16.3% and 18.6%, respectively (p = NS). CONCLUSIONS Hirudin is a promising agent compared with heparin as adjunctive therapy with thrombolysis for acute myocardial infarction, and its evaluation in larger trials is warranted.

Predictors of early morbidity and mortality after thrombolytic therapy of acute myocardial infarction. Analyses of patient subgroups in the Thrombolysis in Myocardial Infarction (TIMI) trial, phase II.

Background Thrombolysis has altered treatment of acute myocardial infarction (AMI). Therefore, reevaluation of predictors of outcome and treatment strategies is appropriate. Methods and Results Clinical variables collected prospectively for the 3,339 patients of the Thrombolysis in Myocardial Infarction II study were analyzed retrospectively to identify predictors of clinical events at 42 days and earlier and to identify subgroups in which an invasive or conservative strategy might be superior. Pulmonary edema/cardiogenic shock presented as the strongest independent correlate with death (relative risk, 6.0). In two subgroups, mortality differed between the invasive and conservative strategies: 1) Patients with versus without prior AMI had a higher mortality in the conservative strategy (11.5% versus 3.5%, p < 0.001); in the invasive strategy, the mortality rates were similar (6.0% and 5.1%). 2) Patients with diabetes mellitus and no prior AMI had a higher mortality in the invasive than in the conservative strategy (14.8% versus 4.2%, p < 0.001). Reinfarction was not independently correlated with baseline characteristics except with history of angina (relative risk, 1.9). Mortality was lower in current smokers and ex-smokers versus never-smokers (3.6% and 4.8% versus 8.0%, p < 0.001). Current smokers had a lower risk profile (p < 0.001), including age, pulmonary edema/cardiogenic shock, history of hypertension, and diabetes. The rate of reinfarction was lower in current smokers versus ex-smokers and never-smokers (4.6% versus 8.3% and 8.8%, p < 0.001). “Not current smoker” was an independent correlate with reinfarction (relative risk, 1.9). The coronary anatomy did not differ among the current smokers, ex-smokers, and never-smokers. Conclusions The strong independent correlation of pulmonary edema/cardiogenic shock with death suggests that thrombolysis is not sufficient to improve survival in these patients. The higher mortality in patients with versus without prior AMI in the conservative strategy suggests that early catheterization and revascularization of these patients might be beneficial. Conversely, the higher mortality in diabetics without prior AMI in the invasive than in the conservative strategy suggests that early aggressive management might not be suitable in this subgroup except for clinical indications. Reinfarction was not predictable by clinical variables except by history of angina. The finding that “not current smoker” was an independent correlate with reinfarction was unexpected.

Prevention of contrast induced nephropathy: Recommendations for the high risk patient undergoing cardiovascular procedures

Contrast induced nephropathy (CIN) is the third leading cause of hospital aquired renal failure and is associated with significant morbidity and mortality. Chronic kidney disease is the primary predisposing factor for CIN. As estimated glomerular filtration rate <60 ml/1.73 m2 represents significant renal dysfunction and defines patients at high risk. Modifiable risk factors for CIN include hydration status, the type and amount of contrast, use of concomitant nephrotoxic agents and recent contrast administration. The cornerstone of CIN prevention, in both the high and low risk patients, is adequate parenteral volume repletion. In the patient at increased risk for CIN it is often appropriate to withhold potentially nephrotoxic medications, and consider the use of n‐acetylcysteine. In patients at increased risk for CIN the use of low or iso‐osomolar contrast agents should be utilized and strategies employed to minimize contrast volume. In these patients serum creatinine should be obtained forty‐eight hours post procedure and it is often appropriate to continue withholding medications such as metformin or non steroidal anti‐inflammatories until renal function returns to normal.

Determinants of coronary blood flow after thrombolytic administration

OBJECTIVES This study evaluated the determinants of coronary blood flow following thrombolytic administration in a large cohort of patients. BACKGROUND Tighter residual stenoses following thrombolysis have been associated with slower coronary blood flow, but the independent contribution of other variables to delayed flow has not been fully explored. METHODS The univariate and multivariate correlates of coronary blood flow at 90 min after thrombolytic administration were examined in a total of 2,195 patients from the Thrombolysis in Myocardial Infarction (TIMI) 4, 10A, 10B and 14 trials. The cineframes needed for dye to first reach distal landmarks (corrected TIMI frame count, CTFC) were counted as an index of coronary blood flow. RESULTS The following were validated as univariate predictors of delayed 90-min flow in two cohorts of patients: a greater percent diameter stenosis (p < 0.0001 for both cohorts), a decreased minimum lumen diameter (p = 0.0003, p = 0.0008), a greater percent of the culprit artery distal to the stenosis (p = 0.03, p = 0.02) and the presence of any of the following: delayed achievement of patency (i.e., between 60 and 90 min) (p < 0.0001 for both cohorts), a culprit location in the left coronary circulation (left anterior descending or circumflex) (p = 0.02, p < 0.0001), pulsatile flow (i.e., reversal of flow in systole, a marker of heightened microvascular resistance, p = 0.0003, p < 0.0001) and thrombus (p = 0.002, p = 0.03). Despite a minimal 16.4% residual stenosis following stent placement, the mean post-stent CTFC (25.8 ± 17.2, n = 181) remained significantly slower than normal (21.0 ± 3.1, n = 78, p = 0.02), and likewise 34% of patients did not achieve a CTFC within normal limits (i.e., <28 frames, the upper limit of the 95th percent confidence interval previously reported for normal flow). Those patients who failed to achieve normal CTFCs following stent placement had a higher mortality than did those patients who achieved normal flow (6/62 or 9.7% vs. 1/118 or 0.8%, p = 0.003). CONCLUSIONS Lumen geometry is not the sole determinant of coronary blood flow at 90 min following thrombolytic administration. Other variables such as the location of the culprit artery, the duration of patency, a pulsatile flow pattern and thrombus are also related to slower flow. Despite a minimal 16% residual stenosis, one-third of the patients treated with adjunctive stenting still have a persistent flow delay following thrombolysis, which carries a poor prognosis.OBJECTIVES This study evaluated the determinants of coronary blood flow following thrombolytic administration in a large cohort of patients. BACKGROUND Tighter residual stenoses following thrombolysis have been associated with slower coronary blood flow, but the independent contribution of other variables to delayed flow has not been fully explored. METHODS The univariate and multivariate correlates of coronary blood flow at 90 min after thrombolytic administration were examined in a total of 2,195 patients from the Thrombolysis in Myocardial Infarction (TIMI) 4, 10A, 10B and 14 trials. The cineframes needed for dye to first reach distal landmarks (corrected TIMI frame count, CTFC) were counted as an index of coronary blood flow. RESULTS The following were validated as univariate predictors of delayed 90-min flow in two cohorts of patients: a greater percent diameter stenosis (p < 0.0001 for both cohorts), a decreased minimum lumen diameter (p = 0.0003, p = 0.0008), a greater percent of the culprit artery distal to the stenosis (p = 0.03, p = 0.02) and the presence of any of the following: delayed achievement of patency (i.e., between 60 and 90 min) (p < 0.0001 for both cohorts), a culprit location in the left coronary circulation (left anterior descending or circumflex) (p = 0.02, p < 0.0001), pulsatile flow (i.e., reversal of flow in systole, a marker of heightened microvascular resistance, p = 0.0003, p < 0.0001) and thrombus (p = 0.002, p = 0.03). Despite a minimal 16.4% residual stenosis following stent placement, the mean post-stent CTFC (25.8 +/- 17.2, n = 181) remained significantly slower than normal (21.0 +/- 3.1, n = 78, p = 0.02), and likewise 34% of patients did not achieve a CTFC within normal limits (i.e., <28 frames, the upper limit of the 95th percent confidence interval previously reported for normal flow). Those patients who failed to achieve normal CTFCs following stent placement had a higher mortality than did those patients who achieved normal flow (6/62 or 9.7% vs. 1/118 or 0.8%, p = 0.003). CONCLUSIONS Lumen geometry is not the sole determinant of coronary blood flow at 90 min following thrombolytic administration. Other variables such as the location of the culprit artery, the duration of patency, a pulsatile flow pattern and thrombus are also related to slower flow. Despite a minimal 16% residual stenosis, one-third of the patients treated with adjunctive stenting still have a persistent flow delay following thrombolysis, which carries a poor prognosis.

Length of Hospital Stay and Complications After Percutaneous Transluminal Coronary Angioplasty Clinical and Procedural Predictors

BACKGROUND Although several studies have established that the complications of percutaneous transluminal coronary angioplasty (PTCA) are related to clinical and angiographic variables such as advanced age and lesion complexity, it is uncertain whether the use of hospital resources after PTCA also depends on the same baseline variables. The purpose of this study was to identify the factors responsible for prolonged hospital stay after PTCA. METHODS AND RESULTS The study cohort included 591 consecutive patients undergoing conventional balloon angioplasty at nine medical centers in North America. Major or minor complications occurred in 91 patients (15.4%) and were observed to be related to several baseline characteristics, including unstable angina, multivessel coronary artery disease, patient age, and lesion complexity. Compared with a median length of hospital stay of 2.0 days after PTCA (25th, 75th percentiles: 2.0, 4.0) for the entire cohort of patients, the length of stay was increased in patients with unstable angina (3.0 days [2.0, 5.0]; P = .002), multivessel coronary artery disease (3.0 [2.0, 5.5]; P = .001), age > 65 years (3.0 [2.0, 5.5]; P = .02), complex lesions (3.0 [2.0, 6.0]; P = .001), and filling defects (6.0 [2.0, 11.0]; P < .001). The length of stay was more strikingly increased, however, in patients who experienced major or minor PTCA complications, such as emergency bypass surgery (9.0 days [8.0, 18.0]; P < .001), Q-wave or non-Q-wave myocardial infarction (8.0 [6.0, 15.5]; P < .001), transfusion unrelated to bypass surgery (8.0 [4.0, 12.0]; P < .001), or abrupt vessel closure (6.0 [3.0, 10.5]; P < .001). On stepwise multiple linear regression, PTCA complications appeared to be the strongest predictors of length of hospital stay (all P < .001) and overwhelmed the weaker relation between length of stay and several individual baseline variables. Inclusion of a composite clinical risk score (reflecting the presence of unstable angina, multivessel disease, advanced age, complex lesions, or filling defects) in the regression model confirmed that patients with several high-risk baseline variables had a significant increase in length of stay after PTCA (P = .003), but PTCA complications remained the strongest predictors of length of stay. CONCLUSIONS Although PTCA complications were correlated with baseline variables such as unstable angina, multivessel disease, advanced age, complex lesions, and filling defects, excess length of stay after PTCA was most strongly influenced by the development of minor and major PTCA complications. Because patients with several baseline risk factors experienced significantly prolonged hospitalizations, improved selection of patients may contribute to reductions in length of stay after PTCA. A greater reduction in resource use after PTCA, however, would be expected from developing new treatments to decrease PTCA complications rather than limiting the access of patients with unstable angina, advanced age, or complex lesions to PTCA.

Trends in the use of pharmacotherapies for acute myocardial infarction among physicians who design and/or implement randomized trials versus physicians in routine clinical practice: the MILIS-TIMI experience

BACKGROUND Although studies have documented that randomized, controlled trials (RCTs) have a measurable influence on clinical practice, investigators have uncovered important deficiencies in the application of RCT findings to the management of acute myocardial infarction (AMI). Little is known about the extent to which physicians who design and/or implement clinical trials differ from physicians in routine practice in their translation of the literature. METHODS Our aims were to (1) evaluate recent trends in selected treatments of AMI in relation to the publication of RCTs, statistical overviews, and task-force guidelines, and (2) compare prescribing practices in AMI management between physicians in routine clinical practice and physicians who design and/or implement RCTs. We reviewed the use of aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers on entry and at discharge in patients enrolled in the MILIS, TIMI 1, 2, 4, 5, 6, and 9B trials with ST-elevation (and depression in MILIS) myocardial infarction for a period approaching 2 decades (August 1978 to September 1995). We hypothesized that physicians who participate in RCTs apply the findings of the published literature more promptly and thoroughly than physicians in routine practice. RESULTS Use of aspirin, beta-blockers, and angiotensin converting enzyme inhibitors exhibited a statistically significant time-related increase at discharge and, excepting beta-blockers, at enrollment across the trials. Prescription of calcium channel blockers showed a statistically significant decrease at discharge only. For all medications under study, increases and decreases in use associated with publication of clinical data occurred earlier and more steeply for the discharge cohort (prescriptions by physicians participating in RCTs) than for the enrollment cohort (prescriptions by physicians in routine practice). Recent prescribing practices (1994 to 1995) among RCT investigators and their colleagues have higher concordance with published findings than those of physicians in routine practice. CONCLUSIONS Physicians who design and/or implement RCTs translate the results of the medical literature more promptly and to a greater extent than physicians in routine clinical practice. Differences between different physician classes need to be studied further amid efforts to reconfigure health care delivery that currently favor more dominant roles for primary care physicians.

High-dose atorvastatin does not negatively influence clinical outcomes among clopidogrel treated acute coronary syndrome patients—A Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) analysis

BACKGROUND Clopidogrel is inactive in vitro and is metabolized by hepatic cytochrome P-450-3A4 to produce active metabolites. Unlike pravastatin, atorvastatin is a statin that is subject to metabolism by cytochrome P-450-3A4, and drug-drug interactions with other potent inhibitors of this cytochrome system have been demonstrated. However, the clinical impact of this interaction has created debate. METHODS In the PROVE IT-TIMI 22 study, 4162 patients with an acute coronary syndrome within the preceding 10 days were randomly assigned in a 1:1 fashion to pravastatin 40 mg or atorvastatin 80 mg daily. The primary efficacy outcome measure was the time from randomization until the first occurrence of a component of the primary end point: death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization with either percutaneous coronary intervention or coronary artery bypass grafting, or stroke. RESULTS At 30 days, there was a trend for less occurrence of the primary end point in patients randomized to atorvastatin compared with pravastatin, irrespective of whether they were taking clopidogrel. This becomes significant at 2-year follow-up in clopidogrel-treated patients (21.66 % vs 26.18% P = .0091). There was no evidence of interaction in the clopidogrel/no clopidogrel subgroup for the primary end point (interaction P = .65) or the components of the composite. CONCLUSION In conclusion, the beneficial affects of atorvastatin 80 mg in reducing the primary end point at 2 years is independent of coadministration with clopidogrel.

Weight-adjusted dosing of TNK-tissue plasminogen activator and its relation to angiographic outcomes in the thrombolysis in myocardial infarction 10B trial

Fixed doses of thrombolytic agents are generally administered to patients of varying body weights, and the dose-response relation may be confounded by the variability in patient weight. We hypothesized that higher doses of TNK-tissue plasminogen activator (tPA) per unit body weight would be related to improved flow at 90 minutes after thrombolytic administration. A total of 886 patients with acute myocardial infarction were randomized to receive either a single bolus of 30, 40, or 50 mg of TNK-tPA or front-loaded tPA in the Thrombolysis In Myocardial Infarction (TIMI) 10B trial. The dose of TNK-tPA administered was divided by the patients weight to arrive at the TNK-tPA dose (mg) per unit body weight (kg), and patients were stratified into tertiles based on mg/kg of TNK-tPA: low dose, 0.2 to 0.39 mg/kg; mid-dose, 0.40 to 0.51 mg/kg; high dose, 0.52 to 1.24 mg/kg. Flow in the culprit and nonculprit arteries was analyzed using the TIMI flow grades and the corrected TIMI frame count (CTFC). The median CTFC in culprit arteries differed between the tertiles (3-way p = 0.007), with the CTFC being 7.2 frames faster in high-dose than in low-dose patients (43.1 +/- 30.1, median 31.2, n = 171 vs 54.6 +/- 34.8, median 38.4, n = 166, 2-way p = 0.002). Patients in the mid- and high-dose tertiles achieved patency more frequently (TIMI grade 2 or 3 flow) by 60 minutes (p = 0.02), and the 90-minute percent diameter stenosis was less severe in patients in the high- versus low-dose tertile (p = 0.03). In nonculprit arteries, the CTFC was faster in high- than in low-dose tertiles (29.6 +/- 13.4, median 26.9, n = 130 vs 34.7 +/- 16.3, median 32.8, n = 108, 3-way p = 0.03, 2-way p = 0.008). In patients who underwent percutaneous transluminal coronary angioplasty (PTCA), the CTFC in culprit arteries after PTCA was fastest in the high- and mid-dose tertiles than in those receiving low doses (2-way p = 0.05). Thus, higher doses per unit body weight of TNK-tPA result in not only faster culprit artery flow, but also faster nonculprit, global, and post-PTCA flow, which may reflect earlier opening, reduced stunning, or improved microvascular function. The greater effectiveness of thrombolysis must be weighed against any increase in risk.

Coronary angioplasty performed within the thrombolysis in myocardial infarction II study

BackgroundPercutaneous transluminal coronary angioplasty (PTCA) of the infarct-related artery was performed within 42 days of recombinant tissue-type plasminogen activator (rt-PA) administration in 1,414 of the 3,534 patients who participated in the Thrombolysis In Myocardial Infarction (TIMI) II study. Primary angiographic success was obtained in 88.7%, with bypass surgery within 24 hours in 3.3% and death within 24 hours in 0.7% of patients. By 1 year, 25.1% of the 1,414 patients had sustained one or more adverse outcomes including death (3.6%), reinfarction (8.4%), or the need for further revascularization (20%). Methods and Result.Despite these generally favorable results, multivariate testing identified several anatomic and clinical subgroups as having an increased risk ratio (RR) for adverse outcome: Unsuccessful PTCA was more common in patients undergoing protocol-assigned PTCA within 2 hours of rt-PA administration (RR, 2.7; p < 0.001) and in patients over age 70 years (RR, 1.7; p = 0.034). The need for further revascularization within 1 year was increased in the 30.4% of patients with multivessel disease (RR, 2.S;p < 0.001), patients with prior angina (RR, 1.4;p = 0.006), or those undergoing ischemia-driven PITCA within 15 hours of rt-PA administration (RR, 1.7; p = 0.022). The risk of death or recurrent infarction within 1 year was increased by the presence of multivessel disease (RR, 1.6; p = 0.007) or prior angina (RR, 1.5; p = 0.014). ConclusionsThese observations do not necessarily apply to patients undergoing primary PTCA (or PTCA after other thrombolytic agents); however, they do offer a unique yardstick against which to evaluate the results of PTCA in myocardial infarction.