Journal of the American College of Cardiology Vol. 33, No. 2, 1999 © 1999 by the American College of Cardiology ISSN 0735-1097/99/$20.00 Published by Elsevier Science Inc. PII S0735-1097(98)00582-8 Thrombolysis Fatal Cardiac Rupture Among Patients Treated With Thrombolytic Agents and Adjunctive Thrombin Antagonists Observations From the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9 Study Richard C. Becker, MD,* Judith S. Hochman, MD,† Christopher P. Cannon, MD,‡ Frederick A. Spencer, MD,* Steven P. Ball, RN,* Michael J. Rizzo,§ Elliott M. Antman, MD,‡ for the TIMI 9 Investigators Worcester, Massachusetts; New York, New York; Boston, Massachusetts, and West Roxbury, Massachusetts

OBJECTIVES The purpose of this study was to determine the incidence and demographic characteristics of patients experiencing cardiac rupture after thrombolytic and adjunctive anticoagulant therapy and to identify possible associations between the mechanism of thrombin inhibition (indirect, direct) and the intensity of systemic anticoagulation with its occurrence. BACKGROUND Cardiac rupture is responsible for nearly 15% of all in-hospital deaths among patients with myocardial infarction (MI) given thrombolytic agents. Little is known about specific patient- and treatment-related risk factors. METHODS Patients (n ϭ 3,759) with MI participating in the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9A and B trials received intravenous thrombolytic therapy, aspirin and either heparin (5,000 U bolus, 1,000 to 1,300 U/h infusion) or hirudin (0.1 to 0.6 mg/kg bolus, 0.1 to 0.2 mg/kg/h infusion) for at least 96 h. A diagnosis of cardiac rupture was made clinically in patients with sudden electromechanical dissociation in the absence of preceding congestive heart failure, slowly progressive hemodynamic compromise or malignant ventricular arrhythmias. RESULTS A total of 65 rupture events (1.7%) were reported—all were fatal, and a majority occurred within 48 h of treatment. Patients with cardiac rupture were older, of lower body weight and stature and more likely to be female than those without rupture (all p Ͻ 0.001). By multivariable analysis, age Ͼ70 years (odds ratio [OR] 3.77; 95% confidence interval [CI] 2.06, 6.91), female gender (OR 2.87; 95% CI 1.44, 5.73) and prior angina (OR 1.82; 95% CI 1.05, 3.16) were independently associated with cardiac rupture. Independent predictors of nonrupture death included age Ͼ70 years (OR 3.68; 95% CI 2.53, 5.35) and prior MI (OR 2.14; 95%, CI 1.45, 3.17). There was no association between the type of thrombin inhibition, the intensity of anticoagulation and cardiac rapture. CONCLUSIONS Cardiac rupture following thrombolytic therapy tends to occur in older patients and may explain the disproportionately high mortality rate among women in prior clinical trials. Unlike major hemorrhagic complications, there is no evidence that the intensity of anticoagulation associated with heparin or hirudin administration influences the occurrence of rupture. (J Am Coll Cardiol 1999;33:479–87) © 1999 by the American College of Cardiology

Cardiac rupture, most often involving the left ventricular (MI) that is responsible for 10% to 15% of all in-hospital free wall and less frequently the interventricular septum, deaths. Written descriptions of this predominately fatal papillary muscle, right ventricular free wall and atria, is a event can be traced back several centuries to William Harvey well recognized complication of acute myocardial infarction (1647) (1), followed 200 years later by the landmark observations of Malmsten (1861) (2), Winsor (1880) (3), Steven (1884) (4) and Krumbhaar (1925) (5), who linked From the *Cardiovascular Thrombosis Research Center, University of Massachu- the occurrence of cardiac rupture to occlusive coronary setts Medical School, Worcester, Massachusetts; †St. Luke’s/Roosevelt Hospital arterial thrombosis, “softening” of the myocardium and, in a Center, Columbia University, College of Physicians and Surgeons, New York, New York; ‡Brigham and Women’s Hospital, Harvard Medical School, Boston, Massa- majority of cases, recent MI. chusetts; §TIMI Database and Coordinating Center, Veterans Administration The reperfusion era has heightened an existing interest in Medical Center, West Roxbury, Massachusetts. Presented, in part, at the American cardiac rupture. From a recent evaluation of over 350,000 College of Cardiology Meetings in Atlanta, Georgia, March 29–April 1, 1998. Manuscript received April 28, 1998; revised manuscript received September 10, patients with MI, several observations were made (6). First, 1998, accepted October 22, 1998. the overall incidence of cardiac rupture, although decreased 480 Becker et al. JACC Vol. 33, No. 2, 1999 Fatal Cardiac Rupture February 1999:479–87

tically anticoagulated (prothrombin time Ն14 s, activated Abbreviations and Acronyms partial thromboplastin time Ն60 s). ACE ϭ angiotensin-converting enzyme All patients received thrombolytic therapy in the form of aPTT ϭ activated partial thromboplastin time either front-loaded, weight-adjusted tissue plasminogen ϭ CI confidence interval activator (tPA) (12) (maximum dose 100 mg) over 90 min MI ϭ myocardial infarction NRMI-1 ϭ National Registry of Myocardial Infarction or streptokinase (1.5 million U over 60 min). The selection OR ϭ odds ratio of a thrombolytic agent was at the treating physician’s TIMI ϭ Thrombolysis and Thrombin Inhibition in discretion. Patients received 150 to 325 mg of aspirin Myocardial Infarction immediately and daily thereafter and were then randomized ϭ tPA tissue plasminogen activator to receive either heparin or hirudin. Other medications including beta-adrenergic blocking agents, nitrates, calcium channel blocking agents, and angiotensin-converting en- with thrombolytic administration, was responsible for a zyme inhibitors were used at the discretion of the treating greater proportion of in-hospital fatal events, particularly physician. early deaths, than in patients not given thrombolytic agents. Study drug was administered either before or within Second, and in contrast to the prereperfusion era (7–9), 60 min of thrombolysis and was continued for at least 96 h. most cardiac ruptures associated with thrombolytic therapy In TIMI 9A (10) patients received either hirudin occurred within 24 to 48 h of infarction rather than later (0.6 mg/kg bolus, 0.2 mg/kg/h infusion) or heparin Ͻ (days 3 to 5) in the hospital course. (5,000 U bolus, 1,000 U/h for patients 80 kg or 1,300 U/h Ն Although the nonspecific protease, plasmin, by weaken- for patients 80 kg) titrated to a target activated partial ing the collagen-based supporting network in a zone of thromboplastin time (aPTT) of 60 to 90 s. Because the rates extensive myocardial necrosis may be an important of hemorrhage were higher than expected in both treatment biochemical/enzymatic contributor, the associated charac- arms, randomization was suspended after 757 patients had teristics of a “susceptible” myocardium are largely unknown been enrolled (10). In TIMI 9B the hirudin and heparin and the time sequence of cardiac rupture, being similar to dosing was reconfigured as follows: heparin (5,000 U bolus, major hemorrhagic events, raises questions about the con- followed by a continuous infusion of 1,000 U/h); hirudin tribution of baseline patient characteristics and systemic (0.1 mg/kg bolus, followed by a continuous infusion of features, including coagulation status. Indeed an association 0.1 mg/kg/h). Neither the bolus nor the infusion of hirudin between anticoagulant therapy, a common adjunct in cur- was permitted to exceed 15 mg (or 15 mg/h). The target rent thrombolytic strategies, and cardiac rupture has been aPTT was 55 to 85 s with dose adjustments made for both considered (6) but not examined in a large-scale clinical study drugs according to a standardized nomogram. Sam- trial. ples were obtained at 12 and 24 h after treatment initiation The purpose of our study was to determine the overall and daily thereafter for aPTT measurement. All measure- incidence and demographic characteristics of patients expe- ments were performed by either a hospital-based anticoag- riencing cardiac rupture after thrombolytic and adjunctive ulation laboratory or a point-of-care coagulation monitor anticoagulant therapy and to investigate the association (CoaguChek Plus; Boehringer-Mannheim Corporation, between thrombin inhibition, with either heparin or hiru- Indianapolis, IN). Consistency in the method of monitoring din, and the intensity of systemic anticoagulation with the was encouraged within the participating centers. development of rupture. A diagnosis of cardiac rupture was made (by the on-site investigator) at the time of death in patients with electro- METHODS mechanical dissociation or sudden cardiac death in the absence of preceding congestive heart failure, slowly pro- The Thrombolysis and Thrombin Inhibition in Myocardial gressive hemodynamic compromise or malignant ventricular Infarction (TIMI) 9 A and B trials have been described in arrhythmias. All major efficacy and safety end points, detail previously (10,11). Briefly, to be eligible for enroll- including serious adverse events, were reviewed and classi- ment patients were required to have an episode of ischemic fied by the Morbidity and Mortality Classification Com- discomfort lasting Ն30 min within the prior 12 h. Electro- mittee, which was unaware of treatment assignment. cardiographic abnormalities, including either Ն0.1 mV ST segment elevation in two anatomically contiguous leads or a Statistical methods. The frequency of cardiac rupture new left bundle branch block were also required. Patients events was analyzed using the chi-square statistical method. were excluded from study participation if there were con- Comparisons were then made between heparin- and traindications for thrombolytic therapy (prior stroke, active hirudin-treated patients. The time to rupture- and non– bleeding, major surgery within 2 months, confirmed blood rupture-related death was analyzed using survival analysis pressure Ͼ180/110 mm Hg), or if they were Ͻ21 years of methods. age, had a serum creatinine Ͼ2.0 mg/dl, were of child- A logistic regression analysis was used to test the rela- bearing potential, had cardiogenic shock or were therapeu- tionship between cardiac rupture (and nonrupture death) JACC Vol. 33, No. 2, 1999 Becker et al. 481 February 1999:479–87 Fatal Cardiac Rupture

Table 1. Baseline Characteristics (TIMI 9A and TIMI 9B) Death Without Alive Without Cardiac Cardiac Cardiac Rupture/EMD Rupture/EMD Rupture p p p ‡Value* Value† Value (3523 ؍ n) (171 ؍ n) (65 ؍ Variable (n Age (yr) 70.9 Ϯ 1.1 70.6 Ϯ 0.8 59.8 Ϯ 0.2 0.986 0.0001 0.0001 Female gender 39 (60%) 65 (38%) 871 (25%) 0.003 0.0001 0.0001 Weight (kg) 71.8 Ϯ 1.7 74.6 Ϯ 1.2 79.8 Ϯ 0.3 0.297 0.0001 0.0001 Height (cm) 165.3 Ϯ 1.3 168.1 Ϯ 0.8 170.4 Ϯ 0.2 0.090 0.0001 0.0015 Time to treatment (h) 3.92 Ϯ 0.34 3.77 Ϯ 0.25 3.38 Ϯ 0.05 0.701 0.045 0.011 Prior angina 29 (45%) 58 (34%) 1004 (29%) 0.173 0.005 0.096 Prior MI 11 (17%) 51 (30%) 572 (16%) 0.047 0.863 0.0001 Hypertension 32 (49%) 93 (54%) 1188 (34%) 0.557 0.011 0.004 Diabetes mellitus 10 (15%) 39 (23%) 544 (15%) 0.280 1.000 0.013 Current smoker 18 (28%) 52 (30%) 1580 (45%) 0.749 0.010 0.001 Initial systolic BP 132.95 Ϯ 2.52 122.48 Ϯ 1.67 131.02 Ϯ 0.36 0.001 0.430 0.0001 Initial diastolic BP 78.98 Ϯ 1.70 74.52 Ϯ 1.08 78.21 Ϯ 0.23 0.018 0.541 0.0003 Initial pulse 80.05 Ϯ 1.80 84.39 Ϯ 1.58 75.53 Ϯ 0.27 0.171 0.015 0.0001 *Cardiac rupture/EMD versus death without cardiac rupture/EMD. †Cardiac rupture/EMD versus patients alive without cardiac rupture. ‡Death without cardiac rupture/EMD versus patients alive without cardiac rupture. BP ϭ blood pressure (mm Hg); EMD ϭ electromechanical dissociation; MI ϭ myocardial infarction. and clinical variables or covariates (age, gender, height, itors, aspirin, beta-blockers and either oral or intravenous weight, past history of angina, MI or hypertension, time to anticoagulants did not differ between patients with cardiac treatment, thrombolytic agent, anticoagulant [heparin or rupture and those without rupture. hirudin], site of infarction, pretreatment blood pressure, Table 1 summarizes the baseline characteristics for pa- initial pulse, serial aPTT measurements, in-hospital proce- tients with cardiac rupture, those with death from non– dures and medications before treatment and during the cardiac rupture-related causes and patients surviving to 30 study drug infusion). For multivariable analyses, the signif- days after infarction. Patients dying, whether from cardiac icance of each regression variable was adjusted for other rupture or another cause, were older, of lower body weight variables used in the model. and stature, received treatment later, experienced prior angina, had a history of hypertension, were nonsmokers and RESULTS had a higher initial heart rate than patients surviving their infarction. A majority of deaths (90%) occurred within the Baseline characteristics. A total of 3,759 patients were first 5 days. Patients dying from non–rupture-related causes enrolled in the TIMI 9A and 9B studies. There were no when compared to survivors were more likely to be diabetic significant differences in age, cardiac risk factors, site of and have experienced a prior MI. In addition, their initial infarction, prior MI, thrombolytic agent or time from symp- blood pressure (systolic and diastolic) was lower, and their tom onset to the treatment between patients allocated to heart rate was higher. heparin and those allocated to hirudin. The assigned study A comparison of patients dying from rupture- and non– drug was received by 97.2% of patients randomized (9,10). rupture-related events identified female gender and shorter There were a total of 65 (1.7%) cardiac rupture events stature as being particularly prevalent in the former. A multi- reported in TIMI 9—all were fatal. Fifteen (1.9%) were variable linear regression analysis was performed to identify reported in TIMI 9A and 50 (1.6%) in TIMI 9B. Patients potential predictors of cardiac rupture (Fig. 1). Age Ͼ70 years with rupture were older, on average by 10 years, of lower (odds ratio [OR] 3.77; 95% confidence interval [CI] 2.06, body weight and stature and more likely to be female than 6.91), female gender (OR 2.87; 95% CI 1.44, 5.73) and prior patients without rupture (all p ϭ 0.001). They were also angina (OR 1.82; 95% CI 1.05, 3.16) were independently more likely to have a history of hypertension, be nonsmok- associated with rupture. A separate analysis was performed to ers and receive treatment later. An anterior site of infarction determine the predictors of nonrupture death at 30 days (Fig. was documented more often than other sites in patients with 2). Age Ͼ70 years (OR 3.68; 95% CI 2.53, 5.35), initial pulse rupture, and although Q waves were present on the elec- Ͼ100 beats per minute (OR 3.08; 95% CI 2.02, 4.70) and trocardiogram in a majority of cases, nearly one out of every prior MI (OR 2.14; 55% CI 1.45, 3.17) were independently three patients did not develop Q waves prior to the event. associated with death not related to cardiac rupture. The admission heart rate was higher in patients who subsequently experienced cardiac rupture; however, there Timing of cardiac rupture. Patients with cardiac rupture were no differences in the presenting systolic and diastolic died earlier in the hospital course than patients dying from blood pressures. The prerandomization use of ACE inhib- non–rupture-related causes (median 1.5 [range 0 to 15] days 482 Becker et al. JACC Vol. 33, No. 2, 1999 Fatal Cardiac Rupture February 1999:479–87

Figure 1. Multivariable analysis of patients experiencing cardiac rupture or electromechanical dissociation (EMD) identified age Ն70 years, female gender and prior angina as independent predictors of an in-hospital event. versus 3.7 [range 0 to 27] days; p ϭ 0.0001). Cardiac been given aspirin (84% vs. 97%; p ϭ 0.09), oral beta- rupture was analyzed separately after dividing events into blockers (3.2% vs. 35.4%; p Ͻ 0.001) and ACE inhibitors those occurring within 24 h of treatment initiation and (6.5% vs. 18.5%; p ϭ 0.02) during the study drug infusion those occurring after 24 h of treatment. There were no compared to those experiencing rupture at a later time significant differences in the timing of rupture based on (Ͼ24 h). Compared with patients who survived their MI, clinical features, initial clinical assessment, site of infarction, patients experiencing cardiac rupture received beta-blockers, thrombolytic agent, time to treatment, thrombin antagonist ACE inhibitors or both less often during the 96-h study (heparin, hirudin) or the combination of thrombolytic and drug infusion. The difference was most notable for patients thrombin antagonist (data not shown). with cardiac rupture during the initial 24 h, in whom ACE A comparison of rupture events either within or after 24 h inhibitors and beta-blockers were administered to 6.5% and of treatment according to medications received prior to 3.2% of patients, respectively. From a total of 31 rupture hospital admission identified a trend toward reduced pre- events that were recorded, no patient had received both an hospital aspirin use among patients experiencing rupture ACE inhibitor and beta-blocker. Patients dying from any within 24 h (10%) as compared to those experiencing cause (rupture and non–rupture related), were less likely to rupture after 24 h (24%) (p ϭ 0.19); however, there were no have received a beta-blocker or an ACE inhibitor than those differences in the use of beta-blockers, ACE inhibitors, surviving their infarction. By multivariable analysis ACE nitrates or calcium channel blockers. In contrast, patients inhibitor or beta-blocker use were inversely associated with experiencing early rupture (Յ24 h) were less likely to have cardiac rupture (OR 0.27; 95% CI 0.16, 0.46; p Ͻ 0.001).

Figure 2. Multivariable analysis of patients with non–rupture-related death. Female gender was not independently associated with non–cardiac rupture death. JACC Vol. 33, No. 2, 1999 Becker et al. 483 February 1999:479–87 Fatal Cardiac Rupture

Table 2. Patients With In-Hospital Death According to Treatment Group Heparin Hirudin Cardiac Rupture Cardiac Rupture/EMD p p p Yes No Yes No Value* Value† Value‡ Age (yr) n 27 41 22 60 0.07 0.94 0.84 Mean 72.8 Ϯ 9.03 68.6 Ϯ 9.51 70.0 Ϯ 9.08 69.8 Ϯ 11.56 Gender Male 12 (44.4%) 26 (64.3%) 8 (36.4%) 37 (61.7%) 0.007 0.004 0.312 Composite aPTT (s) Mean 47.4 Ϯ 20.25 53.5 Ϯ 23.60 46.9 Ϯ 21.28 51.1 Ϯ 22.98 0.305 0.561 0.921 Median 48.0 47.0 52.5 Range 20 to 82 24 to 102 18 to 110 *Compares heparin-treated patients with and without cardiac rupture. †Compares hirudin-treated patients with and without cardiac rupture. ‡Compares heparin- and hirudin-treated patients with cardiac rupture. aPTT ϭ activated partial thromboplastin time, composite (12- and 24-h aPTT values); EMD ϭ electromechanical dissociation.

Thrombin antagonist and intensity of anticoagulation. DISCUSSION Patients experiencing death from rupture- and non–rupture- related causes based on randomization to either heparin or Cardiac rupture is an early and predominantly fatal compli- hirudin are summarized in Table 2. There was no difference in cation of acute MI that occurs in approximately 1% of the overall incidence of cardiac rupture death between heparin- patients but is responsible for nearly 15% of all deaths. and hirudin-treated patients. The intensity of anticoagulation, Thrombolytic therapy accelerates the occurrence of rupture as determined by the aPTT at 12 and 24 h, did not differ to within 24 to 48 h of treatment. Despite an early between patients with cardiac rupture- and non–rupture- clustering of events that could potentially be interpreted as related death. Similarly, the corresponding aPTT values at representing a major bleeding complication, our study baseline, 12 h, 24 h, 48 h and 72 h for patients with and those including over 3,700 patients treated with thrombolytics, without cardiac rupture did not differ (Fig. 3). aspirin and adjunctive thrombin antagonists failed to iden- By multivariable analysis neither heparin, hirudin nor an tify an association between cardiac rupture, the mechanism aPTT greater than 90 s at any time point was independently of thrombin inhibition and the intensity of systemic anti- associated with cardiac rupture. coagulation. We were able to show, however, that cardiac

Figure 3. Serial coagulation measurements (activated partial thromboplastin times [aPTT]) for patients with and without cardiac rupture–related death and those surviving to hospital discharge. There were no differences in the intensity of anticoagulation at the 12-, 24-, 48- and 72-h sampling time points. 484 Becker et al. JACC Vol. 33, No. 2, 1999 Fatal Cardiac Rupture February 1999:479–87 rupture as a cause for early death is particularly common in Thrombin inhibition, intensity of anticoagulation and women and the elderly, providing a mechanistic basis for the cardiac rupture. Hemorrhagic infarction, defined grossly higher mortality among women with MI compared to men as visible blood within the myocardium, is a pathologic that has been reported previously in large-scale thrombolytic feature that coexists with areas of extensive coagulative trials and registries. Lastly, our findings suggest that early necrosis (the end product of severe, persistent ischemia ACE inhibitor and/or beta-blocker administration may found commonly within the center of the infarct zone). reduce the occurrence of cardiac rupture after thrombolytic Although recognized by pathologists for decades, hemor- therapy. rhagic infarction has become a more common occurrence with the advent of thrombolytic therapy (31), and some Early mortality and cardiac rupture in women. Several have suggested that cardiac rupture is the direct result of investigative groups have reported higher mortality rates for myocardial hemorrhage extending through planes of ne- women compared to men with acute MI receiving throm- bolytic therapy (13–19). In TIMI 2 (13), the 6-week crotic and nonnecrotic myocardium (32). If myocardial mortality was 9% for women and 4% for men (adjusted hemorrhage is a prerequisite for cardiac rupture, the con- relative risk 1.54). Overall, women were older and had a comitant administration of anticoagulant therapy, particu- greater prevalence of prior congestive heart failure, systemic larly in high doses, could have a facilitatory effect among hypertension and diabetes mellitus than men suffering an patients with transmural necrosis (33–43). infarction. However, mortality was higher among women There is no evidence from either experimental models or than men in all age strata and persisted after adjustment for clinical trials that anticoagulation exerts a direct effect on the differences in baseline characteristics. The National Registry myocardium after infarction (44). In our study of over 3,700 of Myocardial Infarction (NRMI-1) reported a higher patients with acute MI given thrombolytics, aspirin and in-hospital mortality in women than in men (6.8 vs. 3.0%) adjunctive anticoagulant therapy we were unable to identify even after adjusting for age. Lower body weight (Ͻ70 kg) an association between the mechanism of thrombin inhibi- was also independently associated with in-hospital mortality tion (indirect via antithrombin-mediated neutralization or (20). direct), intensity of anticoagulation and cardiac rupture. To Among 350,755 patients enrolled in NRMI-1, 122,243 the best of our knowledge this is the first study in the received thrombolytic therapy. Although cardiogenic shock reperfusion era to investigate the potential effect of antico- (pump failure) was the most common cause of death, agulation on rupture events among patients receiving cardiac rupture was responsible for 12.1% of deaths com- thrombolytic therapy. Despite a clear association between pared to 6.1% in patients with MI not receiving thrombo- the intensity of anticoagulation and major hemorrhage as lytic therapy. By multivariable analysis thrombolytic agents, reported in several clinical trials (45,46), we did not uncover prior MI, advancing age and female gender were indepen- a similar relationship with cardiac rupture even with doses dently associated with cardiac rupture (9). The Gruppo of heparin and hirudin that lead to a marked increase of Italiano per lo Studio della Streptochinasi nell’Infarcto bleeding events. Although several studies performed in the Miocardico-2 investigators also found a strong association prereperfusion era reached a different conclusion, most were between female gender, increasing age and death due to nonrandomized retrospective analyses, the level of antico- cardiac rupture (21). Patients greater than 70 years of age agulation was excessive and poorly regulated by current who died and underwent autopsy (84 patients) were found standards and the focus was on hemorrhagic pericardial to have cardiac rupture nearly 90% of the time. effusions rather than cardiac rupture (34,35,38,39). Thus, Our group is the first to provide data showing that the we conclude that cardiac rupture, as a pathologic event increased risk of death for women experiencing MI may be involving the myocardium, is not a hemorrhagic complica- attributable to cardiac rupture. By multivariable analysis, tion directly related to antithrombotic therapy. female gender was independently associated with rupture death; however, it was not an independent predictor of Concomitant pharmacologic therapy and cardiac rup- death due to non–rupture-related causes. The predisposi- ture. In TIMI 9, patients experiencing early cardiac rupture tion of women with MI who receive thrombolytic therapy to (within 24 h of treatment) were less likely to have received early cardiac rupture may be attributable to a susceptible oral beta-blockers and ACE inhibitors during the drug collagen framework within the infarcted myocardium. infusion study period than patients who had late rupture. Plasmin-mediated collagen degradation (22–26) and early Further, patients with rupture (at any time) were treated less metalloprotease activation (27), by weakening the support- often with ACE inhibitors and beta-blockers than patients ive connective tissue matrix, undoubtedly contribute to the who survived their infarction. Zones of extensive myocardial process of rupture. Plasmin generation is increased among necrosis are characterized by a marked reduction in collagen patients of low body weight (even with weight-adjusted fibers (22,26); a process that begins within hours of infarc- dosing) (28) and the collagen matrix itself is thought to tion (47). Early infarct expansion and thinning developing differ between women and men (29), particularly with within these areas predispose to both cardiac rupture, as an advancing age (30). early manifestation of extensive collagen loss, and chamber JACC Vol. 33, No. 2, 1999 Becker et al. 485 February 1999:479–87 Fatal Cardiac Rupture dilation with or without aneurysm formation, as a late Although it is likely that most fatal events occur suddenly, feature of a weakened collagen supportive framework. it is possible that type I ruptures (small slit-like tears) Therapies to prevent early infarct expansion have focused progress over several hours, making both the duration and predominantly on ACE inhibitor use in various patient the intensity of anticoagulation important rather than one or subsets, including those with or without clinical signs and two isolated readings. These factors may have limited our symptoms of congestive heart failure (48,49) when started ability to determine the association between aPTT and within (50) or after (51,52) 24 h of infarction. Our findings cardiac rupture but should not have influenced our analysis are consistent with those from a previously reported clinical comparing heparin and hirudin. It is likely that the overall trial (50); however, confirmation of the apparent protective low cardiac rupture event rate in TIMI 9 limited our ability role of ACE inhibitors in patients receiving thrombolytic to detect modest influences attributable to thrombin inhi- therapy will require further investigation. Whether women bition and/or the intensity of anticoagulation. (particularly those greater than 70 years of age) and men The apparent protective effect derived from ACE inhib- derive similar or differing degrees of benefit must also be itors and oral beta-blockers also may have been influenced studied. The impact of beta-blocker therapy will be more by the time sequence of cardiac rupture. Patients experienc- difficult to elucidate with one early trial suggesting a ing rupture within the initial 24 h had less time to have been protective effect (53) and a more recent study (54) showing treated, and their rapid decline in hemodynamic status may no difference in the incidence of cardiac rupture between have influenced management decisions. The use of ACE patients given beta-blockers early versus those treated later. inhibitors and beta-blockers was not randomized, and Unfortunately, the small number of events in TIMI 9 does therefore firm conclusions should not be drawn. not permit us to draw firm conclusions. Lastly, in our study, all reported ruptures were fatal. It is possible that this led to an underestimation of the number of Study limitations. The diagnosis of cardiac rupture was events and the overall impact of anticoagulation (57). based on clinical rather than strict pathologic (necropsy) Although cardiac rupture is predominantly fatal, clinicians findings. It is possible that the number of events was must remain aware that subacute cardiac rupture with overestimated; however, prior large-scale clinical trials with tamponade if diagnosed early is potentially treatable. autopsy-confirmed cases have shown that a clinical diagno- sis of cardiac rupture can be accurate (55), particularly when Conclusions. Women with MI who receive thrombolytic patients with evidence of early pump failure who subse- therapy appear to be at increased risk for early cardiac quently experience electromechanical dissociation and death rupture, providing a mechanistic explanation for their are excluded (56). Our analyses focused on fatal cardiac higher mortality when compared with men. Despite a rupture, which is most often caused by disruption of the recognized association between adjunctive anticoagulant myocardial free wall. Regardless, this potential limitation is therapy and hemorrhagic complications, the available evi- unlikely to have influenced comparative event rates between dence suggests that thrombin inhibition and the overall treatment groups, varying levels of anticoagulation or gen- intensity of systemic anticoagulation do not directly influ- ders. ence the occurrence of rupture. The early protective effects The absence of standardized or normalized methods for of ACE inhibitors and beta-blockers warrant further inves- aPTT measurement is a limitation for all large-scale clinical tigation. trials attempting to investigate an association between coagulation status and clinical events. The method for Reprint requests and correspondence: Richard C. 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