A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement.

BACKGROUND: Despite the use of warfarin, major systemic embolism remains an important complication in patients with heart-valve replacement. Although the addition of antiplatelet agents has the potential to reduce this complication, their efficacy and safety when given in combination with warfarin are uncertain. METHODS: In a randomized, double-blind, placebo-controlled trial, we assessed the efficacy and safety of adding aspirin (100 mg per day) to warfarin treatment (target international normalized ratio, 3.0 to 4.5) in 370 patients with mechanical heart valves or with tissue valves plus atrial fibrillation or a history of thromboembolism. RESULTS: A total of 186 patients were randomly assigned to aspirin and 184 to placebo, and they were followed for up to 4 years (average, 2.5). Major systemic embolism or death from vascular causes occurred in 6 aspirin-treated patients (1.9 percent per year) and 24 placebo-treated patients (8.5 percent per year) (risk reduction with aspirin, 77 percent; 95 percent confidence interval, 44 to 91 percent; P < 0.001). Major systemic embolism, nonfatal intracranial hemorrhage, or death from hemorrhage or vascular causes occurred in 12 patients assigned to aspirin (3.9 percent per year) and 28 patients assigned to placebo (9.9 percent per year) (risk reduction, 61 per cent; 95 percent confidence interval, 24 to 80 percent; P = 0.005); major systemic embolism or death from any cause occurred in 13 patients (4.2 percent) and 33 patients (11.7 percent), respectively (risk reduction, 65 percent; 95 percent confidence interval, 33 to 82 percent; P < 0.001); and death from all causes occurred in 9 patients (2.8 percent) and 22 patients (7.4 percent), respectively (risk reduction, 63 percent; 95 percent confidence interval, 19 to 83 percent; P = 0.01). Bleeding occurred in 71 patients in the aspirin group (35.0 percent), as compared with 49 patients in the placebo group (22.0 percent) (increase in risk, 55 percent; 95 percent confidence interval, 8 to 124 percent; P = 0.02); major bleeding occurred in 24 and 19 patients, respectively (increase in risk, 27 percent; 95 percent confidence interval, -30 to 132 percent; P = 0.43). CONCLUSIONS: In patients with mechanical heart valves and high-risk patients with prosthetic tissue valves, the addition of aspirin to warfarin therapy reduced mortality, particularly mortality from vascular causes, together with major systemic embolism. Although there was some increase in bleeding, the risk of the combined treatment was more than offset by the considerable benefit.

Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement.

After tissue heart valve replacement 108 patients were randomised to standard anticoagulant control with rabbit brain thromboplastin (Dade C reagent, therapeutic range 18-24 s; international normalised ratio 2.5-40) and 102 to a less intensive regimen controlled with human brain thromboplastin (Manchester Comparative Reagent, therapeutic range 26-30 s; INR 2.0-2.25). Treatment was continued for three months, outcome measures being major or minor embolism or haemorrhage. 2 patients in each group had major embolic events and 11 in each group had minor embolic events. The 95% confidence intervals on the differences are -3.4% to 3.2% for major embolism and -9.3% to 8.2% for minor embolism. Haemorrhagic complications were significantly more frequent with standard treatment (15 patients) than with the less intensive regimen (6 patients); and of the 5 patients with major haemorrhagic complications, all were in the standard treatment group, again a significant difference. The less intensive regimen is thus no less effective and safer than standard anticoagulant therapy in patients with tissue heart valve replacement.

Inability of caliper measurement to enhance observer agreement in the interpretation of coronary cineangiograms.

Important clinical decisions are made on the basis of the interpretation of the degree of stenosis in the coronary cineangiogram. Thus, minimization of observer variation (both intra and inter) is crucial. The purpose of this investigation was to determine if measurement of stenotic lesions by caliper (CM) as compared with the usual eyeball method (EM) would reduce observer variation. Five observers, using the AHA scoring system, estimated maximal luminal narrowing in 14 segments on 10 films providing 2 reports on each film by EM and 2 by CM, thus making observations on 2800 segments. This allowed analysis of intraobserver variation for each reporter for method EM and CM, and for interobserver variation by each method. Since chance agreement is an important component in an observational study, a correction for this was made using the Kappa statistic. The results revealed that the mean Kappa by EM was 0.71 compared to 0.63 by CM (1 being perfect agreement and 0 no agreement). Agreement was much greater in proximal rather than distal segments. Interobserver agreement was consistently higher by EM K = 0.62 than CM K = 0.53 (p = 0.0007). A delineation of the types of disagreement and their clinical significance are important considerations in the evaluation of observer variation. It is concluded that the use of a caliper does not enhance either intra or interobserver agreement.

Effect of suloctidil on platelet function in patients with shortened platelet survival time.

The effect of suloctidil (600 mg/day) on platelet survival time (PST) and plasma and urine betathromboglobulin (BTG) was studied in a double-blind, placebo-controlled six-week crossover trial in 13 patients with shortened PST (less than 110 hrs, exponential model). Mean PST after suloctidil (110.6 hrs) was significantly higher than in the placebo phase (94.5 hrs) (p = 0.04). Mean plasma BTG was significantly lower during the suloctidil phase (42.8 ng/ml) compared with the placebo phase (65.8 ng/ml) (p = 0.02), but there was no significant difference in urine BTG. These results suggest that suloctidil provides a platelet protective effect and therefore may be of benefit in reducing the frequency of platelet mediated thromboembolic events.

Early changes in venous arterial autografts: a scanning electron microscope study.

The use of autogenous vein as an arterial substitute has been advocated for many years. Methods of harvesting generally cause spasm of the vein and it has been shown that preventing the spasm by applying papaverine improves long-term patency. The present study was undertaken to see if the reported long-term patency of such grafts was associated with improved short-term appearance of the venous endothelium as viewed with the scanning electron microscope. Two groups of dogs were studied; those sacrificed at 3 hours and those at 24 hours after replacing excised segments of the carotid and femoral arteries with cephalic veins. One of the veins was removed in the standard manner allowing spasm followed by distension back to its pre-spasm state; in the other, spasm was prevented by the topical application of papaverine before removal. The study shows that venous endothelial integrity is preserved by the use of papaverine and this improved appearance of the endothelium persists for the first 24 hours after insertion into an arterial milieu. But the study also demonstrated that there was extensive activity of polymorphonuclear leukocytes associated with the endothelium in the early hours after arterialization and that they appeared to have a deleterious effect on the endothelium.

Intimal hyperplasia in autogenous veins used for arterial replacement.

This study compares the effects on intimal hyperplasia of different methods of manipulating a vein graft before using it as an arterial substitute. Grafts that were denuded of endothelium showed the most intimal hyperplasia, while those that were washed with saline, dilated with saline or crushed did not differ appreciably from each other with respect to the degree of intimal hyperplasia. The hyperplasia was well developed and stabilized at 3 weeks, which coincided with restoration of the endothelial surface. The similarity between the last three methods of graft manipulation suggests that minor endothelial disruption produced at the time of harvesting the vein is equalized after insertion of the vein into the arterial circulation.

Management of intractable ventricular tachyarrhythmias after myocardial infarction.

Twenty-five patients with recent or old myocardial infarction were studied because they had life-threatening ventricular arrhythmias that required repeated cardioversions and were intractable to medical management. All patients had had a large anterior infarction a mean of 4.6 weeks before the emergence of the arrhythmias and all had severe left ventricular dysfunction. Cardiac catheterization or autopsy revealed a left ventricular aneurysm in 18 of 18 patients and obstruction of the left anterior descending coronary artery in 20 of 20 patients. Of 16 patients treated surgically with aneurysm resection or coronary bypass grafting, or both, 10 (62 percent) were alive after 3 to 39 (mean 26) months of follow-up. The perioperative mortality rate was 31 percent and only one patient died during the postoperative follow-up period 4 months after discharge from the hospital. By contrast, all nine medically treated patients died either in the hospital (four patients) or suddenly within 2 months of discharge (five patients). Ventricular fibrillation was documented as the cause of death in five of these patients. Surgical intervention was found to improve significantly the survival of these patients (P less than 0.02). The perioperative mortality rate was lower when at least 4 weeks had elapsed from acute infarction to surgery (10 versus 67 percent) and when the procedure included coronary bypass grafting (13 versus 50 percent), although these differences were not statistically significant (P greater than 0.05).

Subannular mitral prosthesis in aortic position.

Björk-Shiley subannular mitral prostheses have been used in the aortic position in 36 patients with calcific aortic annulus. We believe that the flange in the sewing ring of these prostheses offers added protection against perivalvular leakage; over an 18-month period there have been no instances of periprosthetic leakage in these patients.

Evolving indications for preoperative intraaortic balloon pump assistance.

Over a two-year period about 1,000 operations were performed with cardiopulmonary bypass. Intraaortic balloon pump assistance (IABP) was employed on 150 occasions, and a review of these has permitted clarification of the indications for its use. Sixty patients had IABP for carcinogenic shock either after infarction or cardiotomy, and 37 (62%) survived. Preoperative IABP in 90 high-risk patients resulted in survival for 79 (88%). The indications for prophylactic IABP included: (1) relief of severe pain, which occurred in 42 patients with acute coronary insufficiency, (2) improvement in the coronary perfusion pressure, which was accomplished in 20 patients with significant left main coronary artery occlusion or its equivalent, and (3) protection of left ventricular function, which war carried out in 28 patients with an LV ejection fraction of less than 0.40. The significance of the preoperative endocardial viability ratio (EVR) in relation to prophylactic IABP was also assessed: an EVR below 0.70 appears to be an indication for preoperative IABP.

Surgical management of complicated acute coronary insufficiency.

Acute coronary insufficiency (ACI) has a one year mortality rate approximating 40 percent with medical treatment alone. This report reviews our experience over 24 months with preoperative intra-aortic balloon pump assist (IABPA) in 42 patients with ACI. Abnormal left ventricular (LV) hemodynamics were present in the majority of patients; the ejection fraction was less than 40 percent in 14 patients. The endocardial viability ratio (EVR) was less than 0.7 in eight patients. The mean coronary artery score was 13, compared to 9 in an otherwise comparable group of patients with stable angina. Left main coronary stenosis greater than 75 percent was present in seven patients and combined with significant stenosis (less than 72 percent) in the dominant right system in four patients. Four patients had proximal stenoses greater than 90 percent in all three major coronary arteries. IABPA was initiated in 11 patients prior to angiography because of refractory rest pain. One of these six patients died. Twenty-five other patients were supported before and six after induction of general anesthesia. Thirty-three of 36 revascularized patients survived. Of four patients with perioperative myocardial infarctions (12 percent), three had IABPA after induction of general anesthesia. Inotropic support and duration of stay both in intensive care and in the hospital were less than in similar patients treated before the use of IABPA.

Aortocoronary bypass made possible by coronary endarterectomy.

Thirty bypass grafts to coronary arteries were made possible by manual core endarterectomy. The overall patency rate of the grafts was 57%, which is less than the patency rate of bypass grafts to nonendarterectomized vessels (75 to 80%). In the perioperative period and during follow-up to 29 months there was no increase in mortality or morbidity even when the endarterectomized vessel subsequently became occluded. These results represent early technical experience. Routine anticoagulant therapy in the postoperative period, to prevent early occlusion, was not used. The results of this and other studies suggest that coronary endarterectomy with bypass grafting is a useful procedure in situations where the coronary artery is so severely obstructed that standard saphenous vein bypass grafting cannot be performed; the procedure is superior to coronary endarterectomy alone.

Prognostic significance of endocardial viability ratio in aortocoronary bypass surgery.

Although aortocoronary bypass (ACB) for patients with stable angina carries a low mortality, some unexpected deaths do occur. Since in patients with normal coronary arteries the endocardial viability ratio (EVR) can be correlated with subendocardial perfusion, with a ratio of 0.7 or less indicating ischemia of the left ventricular subendocardium, and since the EVR postoperatively is useful in determining the need for intra-aortic balloon pump assist (IABPA), it was decided to ascertain whether the EVR might have prognostic value in patients with stable angina scheduled for standard ACB. Three groups of patients were studied: 50 with stable angina, 24 who had died after ACB, and 18 who required IABPA for cardiogenic shock after surgery for stable angina. No significant differences were found for cardiac index, left ventricular end-diastolic pressure, left ventricular ejection fraction and pre- and postoperative artery scores, but there were significant differences in the EVR between the first and second groups and between the first and third groups (P less than 0.01 in each instance). These findings suggest that the left ventricular EVR may indeed be of prognostic value in patients scheduled to undergo ACB and that use of IABPA, which produces an increase in EVR, may be useful in patients with EVRs of less than 0.7, even if other parameters of cardiac function are normal.

Intra-aortic balloon pump assist: adjunct to surgery for left ventricular dysfunction.

Intra-aortic balloon pump assist (IABPA) was used intraoperatively and postoperatively in 34 patients with severe left ventricular dysfunction: the mean ejection fraction was 0.29 and all patients had angiographic grade IV left ventricular contractility. There were three groups of patients: 11 patients with acute coronary artery insufficiency--10 of whom survived vein bypass surgery (group 1); 16 patients with crescendo-type unstable angina--of whom 15 survived surgery (group 2); 7 patients with single (6) or multivalvular (1) replacement (combined with vein bypass in 3)--of whom 5 survived (group 3). Overall survival was 88%. The mean duration of 1:1 IABPA was 40 hours. Inotropic support was not required, hemolysis was insignificant and hemostasis remained secure. Two patients required tracheostomy and one required dialysis. One patient had a peripheral embolus in the leg used for IABPA. IABPA improves subendocardial perfusion during induction of anesthesia, during cardiopulmonary bypass and into the postoperative period; left ventricular work is decreased with a concomitant increase in coronary artery and vein graft blood flow. Use of IABPA may also improve survival and lessen morbidity in patients with left ventricular dysfunction due to the beneficial effects on myocardial performance and is thus a valuable adjunct to cardiac surgery in high-risk patients.

Increasing operability and survival with intra-aortic ballon pump assist.

Intra-aortic ballon pump assist (IABPA) was used over a 12-month period in the management of 41 patients: 5 patients with complications of myocardial infarction in shock whose circulation was supported by IABPA before operation immediately after angiographic and hemodynamic study (group 1); 14 patients with postcardiotomy low-output state who could not be weaned from cardiopulmonary bypass and required IABPA circulatory support either in the operating room or in the intensive care area (group 2); 19 patients with severe myocardial ischemia and unstable circulation in whom IABPA was instituted either before angiography or before saphenous vein bypass operation (group 3); and 3 patients with severe left ventricular dysfunction and left ventricular hypertrophy due to aortic valve or coronary artery disease, or both, in whom IABPA was used before, during and after cardiopulmonary bypass and a corrective operative procedure (group 4). Survival rates for patients in these groups were 2/5,8/14,18/19 and 2/3 respectively (overall survival, 73%). IABPA may increase the postoperative survival of certain high-risk patients with poor left ventricular function due to valvular disease or coronary artery disease, or both. The survival of patients with severe myocardial ischemia and complicated myocardial infarction is improved by IABPA, early angiography and appropriate surgical correction. Left ventricular ejection fraction and the estimate of subendocardial coronary flow by the ratio of the diastolic pressure time index to the tension time index appear to be significant in identifying patients who may benefit from the use of IABPA.

Ischemic contracture of the left ventricle. Production and prevention.

Ischemic contracture of the left ventricle ("stone heart") is a recognized complication of prolonged periods of interruption of the coronary circulation during open-heart surgery. We have examined the effects of moderate hypothermia (28 degrees C.) and preoperative beta-adrenergic blockade (propranolol, 0.5 mg. per kilogram; 1.0 mg. per kilogram) on contracture development during ischemic arrest of the heart. Four groups of 8 dogs each were placed on total cardiopulmonary bypass, and ischemic arrest of the heart was produced by cross-clamping the ascending aorta and venting the left ventricle. Intramyocardial carbon dioxide tension was continuously monitored by mass spectrometry. When anaerobic energy production ceased, as indicated by a final plateau in the intramyocardial carbon dioxide accumulation curve, the ischemic arrest was terminated and the contractile state of the heart observed. These results are given in the text. We conclude that beta-adrenergic blockade delays, but does not prevent, the onset of ischemic contracture of the left ventricle under normothermic conditions. Moderate hypothermia appears to prevent this complication completely.

The late results of cardiac valve replacement using autologous fascia lata.

Over an eight-month period beginning in November 1969, 53 patients received 63 fascia lata heart valves at the Toronto General Hospital. The late results of this form of valve substitution are reviewed. The fascia used to fashion the tricuspid valve underwent progressive thickening and contracture and this process caused failure of the prosthesis within months of insertion. The mitral fascial prosthesis failed in a similar manner although the process took longer. The aortic fascia lata valve, however, has not shown progressive thickening after 3(1/2) years and it has so far retained its functional integrity. Indeed, we have been impressed by the excellent clinical results and absence of complications such as thromboembolism although anticoagulation has not been used. We therefore consider that fascia lata valves offer a suitable alternative to other forms of aortic valve substitution, but are unsatisfactory for tricuspid or mitral valve replacement.