Ridogrel as an adjunct to thrombolysis in acute myocardial infarction

International Journalof

CARDIOLOGY ELSEVIER

International

Journal of Cardiology

52 (1995) 125-134

Ridogrel as an adjunct to thrombolysis in acute myocardial infarction L.R. van der Wieken*a, M.L. Simoonsb, G.J. Laarmana, M. van den Brandb, K.M. Nijssenb, M. Dellborgc, W. Hermensd, W. Vrolik” aDepartment of Cardiology, Onze Lieve Vrouwe Gasthuis, Ie Oosterparkstraat 279, 1000 HA4 Amsterdam, The Nether/an& bThoraxcenter, Erasmus University and University Hospital Dijkzigt, Rotterdam. The Netherlands ‘Department of Medicine, &tra Hospital, University of Gothenburg. Gothenburg. Sweden ‘Research Institute for Cardiovascular Diseases, Maastricht. The NetherIan& eUniversity Hospital Gasthuisberg, Division of Cardiology, Leuven. Belgium Received 4 January 1995; revision accepted 23 August 1995

Abstract

An open pilot study was performed to assessthe safety and preliminary efficacy of ridogrel, a selectivethromboxaneA, synthetase inhibitor and thromboxane-A,/prostaglandin endoperoxide receptor blocker, as adjunct to thrombolysis with alteplase and heparin. In 50 patients with acute myocardial infarction, 300 mg ridogrel was injected intravenously in addition to alteplase and heparin. Ridogrel was continued orally (300 mg) twice daily for 5 days. Patency rate at initial (90 min) angiography, defined as thrombolysis in myocardial infarction perfusion grades2 or 3, was 86%. Rescue percutaneous transluminal coronary angioplasty was performed in 10 patients; immediate results were good in nine, while a large dissection occurred in one patient. New ischemia occurred in 10 patients within 24 h, and after the second angiogram in seven cases. Three underwent coronary artery bypass grafting and seven percutaneous transluminal coronary angioplasty without further complication. Patency rate at second angiography (between 6 and 24 h) was 94%. New Q-wavesappearedin 56% of the patients; 36%had a non-Q-wave infarction and 8% had no enzyme rise. Enzymatic infarct size, estimated by the cumulative quantity of cr-hydroxybutyrate dehydrogenasereleasedin 72 h, was substantially smaller than in comparable studies with rt-PA and heparin. One patient died due to a cerebrovascular hemorrhage. No other deaths occurred. Bleeding complications were seen in 18 patients (36%) necessitating blood transfusion in three. Reinfarction did not occur. Eventually 49 patients were discharged in good condition. Safety with regard to bleeding complications of ridogrel in conjunction with alteplase is about the sameas that of aspirin. Immediate and late patency rates were high. Rescuepercutaneous transluminal coronary angioplasty could be performed with relative safety and early reocclusion could be successfully dealt with by repeat percutaneous transluminal coronary angioplasty. Further studies with this or similar compounds seemwarranted. Keywords: Myocardial infarction; Thrombolysis; Ridogrel; Thromboxane synthetaseinhibitor; Thromboxane receptor

blocker

* Corresponding

author.

0167-5273/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-5273(95)02476-D

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1. Introduction Thrombolytic therapy has been established as preferred treatment in selectedpatients with acute myocardial infarction. Timely reperfusion results in limitation of infarct size. Thereby the deleterious consequencesof infarction, such as congestive heart failure and death, are prevented or mitigated [l-3]. In addition, patency of the infarct related artery is associatedwith prevention of infarct distension and with improved longterm survival [4]. In spite of this progress, someproblems remain. In some of the patients reperfusion is not achieved within the first l-2 hours after the initiation of therapy, depending on the choice of thrombolytic regimen [5]. Furthermore, early reocclusion of an infarct related vesseloccurs in lo-20% of patients. In patients with failed thrombolysis or reocclusion, percutaneous transluminal coronary angioplasty of the infarct related vesselcan be attempted [6,7]. Platelet aggregation plays a key role in these events. In most patients, the infarct is initiated by plaque rupture, exposing smooth muscle and collagen, which causesplatelets to adhere and to aggregate and activates the clotting cascade [8,9]. Furthermore, coronary thrombolysis results in increasedplatelet activation, which, in the setting of reperfusion and depressed anti-aggregatory prostacyclin (PG12) biosynthesis, may initiate acute reocclusion [ 10, 111. The interaction between platelets and coronary vascular endothelium is believed to depend on the balance between the production of the pro-aggregatory thromboxane (TXA*) by platelets and PGIl by the endothelium

WI. Aspirin, a non-selective inhibitor of cyclo-oxygenase,enhancesthe benefits of thrombolytic therapy [2], probably by inhibition of platelet activation and by facilitation of clot lysis. However, such non-selective inhibition also prevents the formation of prostacyclin. Selective TXA2 synthetase inhibitors decrease the formation of TXA, and increase the synthesis of PG12 and prostaglandin D2 (PGD& [ 131. However, the accumulated endoperoxides (PGH,) limit their efficacy by activating the platelet and/or the vessel wall receptor without mediation of TXA, itself [ 14,151.TXAzreceptor antagonists impede the action of both

Journal of Cardiology 52 (1995) 125-134

TXAz and PGH2 on the platelet and vessel wall receptor, but leave the formation of prostaglandins unchanged. Recently, the combination of TXAz synthetase inhibition with TXAz-receptor antagonism has been proven to exert a greater anti-platelet and anti-thrombotic effect than aspirin [ 16- 181. Ridogrel is such a novel, selective TXAz synthetase inhibitor with TXA2/prostaglandin endoperoxide receptor blocking properties. The anti-thrombotic effects of ridogrel have been evaluated in animals and man [ 191.Previous clinical studies have involved patients undergoing coronary angioplasty [24], patients with unstable angina [25], acute myocardial infarction [26,27], and obstructive arterial diseaseof the lower limb [28]. The current pilot study was designedto assess the safety and preliminary efficacy of ridogrel in patients undergoing thrombolytic therapy with alteplase and heparin. 2. Patients and methods Patients, between21 and 71 years old, with chest pain typical of myocardial infarction for at least 30 min and ST segmentelevation in at least two leads (0.2 mV in leads Vre4 of 0.1 mV in the other leads) were eligible for this trial, provided that experimental treatment could be started within 6 h after onset of symptoms. Exclusion criteria were: use of drugs affecting platelet function such as acetyl salicylic acid in the preceding 7 days, use of oral anti-coagulants, a known bleeding disorder or major bleeding in the preceding 3 months, traumatic resuscitation, requirement of artificial respiration, persistent hypertension at admission (systolic blood pressure > 200 mmHg), known or suspected proliferative diabetic retinopathy, history of nephrolithiasis or clinical signs of hyperuricaemia, child bearing potential, previous Q-wave myocardial infarction in the samelocation, other Q-wave infarction in the preceding 2 weeks,previous coronary bypass surgery, severehepatic, renal, or pulmonary disease, complete bundle branch block and inability to give informed consent. Consenting patients were registered by a central telephone service.

L.R. van der Wieken et al. /International

2.1. Treatment

Patients received a bolus injection of ridogrel 300 mg. i.v. Thereafter, a loading dose of 5000 IU of heparin was given and 10 mg alteplase was administered as a IO-mg bolus injection, followed by an i.v. infusion of 50 mg during the first hour and of 40 mg during the second and third hour [3,6]. Ridogrel was continued orally (300 mg twice daily) until 5 days after admission, starting between 6 and 12 h after the i.v. dose. After 5 days it was advised to give aspirin orally. Heparin was continued for at least 24 h at a rate of 1000 IV/h, which was adjusted to maintain activated partial thromboplastin time (APTT) between 2 and 2.5 times normal. In case of rescue, percutaneous transluminal coronary angioplasty an extra dose of 5000 IU of heparin was administered. Arterial sheaths were removed only after activated partial thromboplastic time had dropped below 1.5 times normal. In addition all patients received glyceryl trinitrate i.v. at a rate of 50-100 pglmin unless systolic blood pressure was < 100 mmHg. Any other treatment was given as clinically indicated. 2.2. Laboratory analysis

Blood sampleswere collected for assessmentof the activities of cardiac enzymes including (Yhydroxybutyrate dehydrogenase (a-HBDH), before the start of trial medication and after 3, 6, 9, 12, 24 and approximately 36, 48, 72 and 96 h. Infarct size was calculated as previously described 1291. 2.3. Cardiac catheterisation

Coronary angiography was performed 90 min after start of thrombolytic therapy and again between 6 and 24 h. Patency of the infarct related vessel was determined according to the thrombolysis in myocardial infarction criteria [30] as non-perfusion (0), penetration with minimal (1) partial perfusion (2) and complete perfusion (3). Arteries graded 0 and 1 were considered to be occluded. In these patients, rescue percutaneous transluminal coronary angioplasty would be attempted. Immediate post-percutaneous transluminal coronary angioplasty angiograms were evaluated along the same standard. All angiograms were re-assessedby a central committee.

Journal of Cardiology 52 (1995) 125-134

2.4. ECG and continuous graphic monitoring

127

vector-electrocardio-

In all patients a standard 1Zlead ECG was recorded at the time of randomization, at 24, 48 and 96 h and before discharge. All ECGs were scrutinized centrally for the development of Qwaves and ST-segment changes. In addition a three-lead (Frank) vector-ECG was recorded continuously during 24 h following admission [3 1,321. The signals were averaged over 2-min periods. STvector magnitude (ST-VM) and QRS-vector difference (QRS-VD) were calculated and presented as trend curves. The QRS-vector difference is the square root of the sum of squares of the areas between the current and the initial QRS complexesin the three leads. This parameter reflects all changes in the QRS-complex. All ST-VM and QRS-VD recordings and the corresponding vectorcardiograms were analyzed by a central committee for WRS and ST-changesduring the 24 h-recordings, with the criteria developed by Delborg [31,32]. Phenomena studied were: the maximum ST-VM during the first 4 h, the mean time to ST-VM decline, the number of episodes of recurrent STVM increase during the first 4 h (early ST variability), the number of ischemic periodes in the 4-14 h interval, the number of ischemic periodes between 14-24 h, and the mean time to QRS-VD plateau. 2.5. Clinical events

All relevant clinical events during hospital stay were recorded and reviewed by the ECG committee. In particular cardiovascular events and bleeding events were described in detail. 3. Results Between January and November 1991, 52 patients were entered in this study. Two patients were excluded from the analysis. One patient withdrew his consent after receiving the bolus injections of alteplase and ridogrel intravenously. In one other patient, an exclusion criterium was recognisedafter allocation, but before therapy was given. Both patients had an uncomplicated couri in hospital. Baseline characteristics of the 50 remaining pa-

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Table 1 Baseline characteristics of 50 patients with myocardial infarction treated with ridogrel, alteplase and heparin n = 50 Age (years) Male gender Anterior ST-elevation Inferoposterior ST-elevation Previous infarct History of angina History of hypertension Current smoker

54 (29-71) 44 (88%) 13 (26%) 37 (74%) 4 (8%) 26 (52%) 5 (10%) 25 (50%)

Data are presented as median value (range), respectively, number (percentage) of patients.

tients are shown in Table 1. On review, ECG entry criteria were met in all patients. The delay between onset of symptoms and infusion of alteplase ranged from 34 to 439 min, median 170 min. The hemodynamic state at admission was normal in 46 patients, one had mild left heart failure and three patients were in cardiogenic shock. All shock patients recovered during their hospital stay. No late heart failure was observed. An infarct with peak creatine kinase exceeding

Table 2 Coronary patency (thrombolysis mittee Initial angiogram

Non-perfusion (TIMI-O) Minimal perfusion (TIMI-1) Partial perfusion (TIMI-2) Complete perfusion (TIMI-3)

Journal of Cardiology 52 (I9951 125-134

twice the normal upper limit or new Q-wave developed in 41 patients. In five patients the peak creatine kinase remained between one and two times the normal value. No enzyme rise was observed in four patients with inferior ST-segment elevation on admission. New Q-waves developed in 28 patients (56%). No reinfarction occurred. One patient developed a haemorrhagic cerebrovascular accident as documented by computer tomography, 2 h after the start of intravenous therapy and died 21 days later. All other patients were discharged alive. 3.1. Initial coronary patency

Angiography was performed in all patients, 102 min (median, range 43-191 min) after initiation of therapy. An infarct related vessel was identified with the aid of the baseline ECG in all but two patients who showed no angiographic abnormalities. In 13 casesthe left anterior descending artery was implied, in seven the left circumflex artery and in 28 the right coronary artery. According to the central committee, patency was 86% (thrombolysis in myocardial infarction perfusion grade 2 or 3; 95% C.I. 73-94%). Complete (thrombolysis in myocardial infarction-3) perfusion was observed in 74% (Table 2).

in myocardial infarction grades) at initial angiography, as assessed by the central angiography com-

All patients

Patients who underwent PTCA directly after the initial angiogram

All patients

First injection (n = 50)

Before PTCA (n = 10)

After PTCA (n = 10)

After initial angio/PTCA (n = 50)

5 2 2* 1**

0 0 1 9

5 2 6 37

0 0 5 45

In two patients the investigators reported minimal perfusion of the infarct related vessel (thrombolysis in myocardial infarction-l), while partial perfusion (thrombolysis in myocardial infarction-2) was scored by the committee (*). Percutaneous transluminal coronary angioplasty was performed in both patients. In one patient with complete perfusion at the first contrast injection, subsequent coronary occlusion occurred and percutaneous transluminal coronary angioplasty was performed (**). Overall initial patency was 86%. Final patency, including 10 patients with percutaneous transluminal coronary angioplasty, was 100%.

L.R. van der Wieken et al. /International reperfusion

The probable timing of coronary reperfusion could be estimated from the vector-ECG trendrecordings (Fig. 1). The data indicate that reperfusion was achieved in 65% of the patients within 40 min.

(%)

3.2. Percutaneous transluminal plasty

20

o 1 -..-.~~~ 0 time

~~~

20 of reDerfusion

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Journal of Cardiology 52 (1995) 125-134

40 of infarct

60 related

60 vessel (mini

100

120

Fig. 1. Examination of timing of reperfusion from continuous vector-electrocardiography, in relation to the start of thrombolytic therapy (time = 0). Angiographic patency (median time of angiography = 102 min) was 86%, (95% CL 73-94%) as indicated by the vertical bar.

coronary angio-

According to the protocol, rescue percutaneous transluminal coronary angioplasty of the infarct related vesselwas attempted in all phaseswith perfusion grades 0 and 1 as judged by the angiographer (Fig. 2). This included two patients in whom the infarct related artery was scored patent by the central review committee, and one other patient with grade 2 perfusion on the first injection of contrast in the infarct related artery while the artery appeared completely occluded on subsequent angiograms. In nine patients rescuepercutaneous transluminal coronary angioplasty resulted in complete (thrombolysis in myocardial infarction-3) perfusion. In one patient atherectomy of the right coronary artery was performed, resulting in partial perfusion (thrombolysis in myocardial infarction-2) with a large dissection. 3.3. Late coronary patencyheocclusion

Second angiogram

Third

1

b

anglogram

Fig. 2. Results of angiography and PTCA. 0 patent, TIMI-II and -III; l occluded, TIMI-O and -I;* No second angiogtram in two patients;# A third angiogram was made in four patients after PTCA at the time of the second angiography.

A secondangiogram was made in 48 patients between 4 and 30 h after initiation of thrombolytic therapy (median 18 h). Angiography was performed between 4 and 7 h after the start of therapy in four patients, becauseof recurrent ischemia. Ridogrel and heparin had been discontinued in one patient for hematemesis,and the vesselappeared occluded. In the other, the vesselswere patent with moderately severestenoses.In all four patients immediate percutaneous transluminal coronary angioplasty resolved the stenoses. In 39 patients the second angiogram was made between 7 and 24 h, and in five patients after 24 h. No repeat angiogram was performed in the patient who developed an haemorrhagic cerebrovascular accident and in the patient with dissection after atherectomy. Reocclusion was observed in only three patients, after initially successfulpercutaneous transluminal coronary angioplasty (Table 3). Complete perfusion (thrombolysis in myocardial infarction-3) was observed in 43 patients, and

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Table 3 Coronary patency (thrombolysis in myocardial infarction grades) at the second angiogram, as assessedby the central angiography committee Second angiographs

All patients Patients without (n = 50) PTCA

Patients with PTCA (n = 10)

(n = 40)

Non-perfusion 3 (TIMI-O) Minimal perfusion 0 (TIMI-I) Partial perfusion 2 (TIMI-2) Complete per43 fusion (TIMI-3) No angio 2

0

3

0

0

2

0

37

6

1*

1**

The median time from start ridogrel infusion until second angiogram was 18 h, range 4-30 h. Reocclusion was observed in three patients, all of whom had undergone percutaneous transluminal coronary angioplasty at the first angiogram. No secondangiogram was made in two patients; * one patient after a cerebrovascular accident and ** one other patient with dissection of the right coronary artery.

thrombolysis in myocardial infarction-2 in two patients. In all patients with a patent vesselwho did not undergo percutaneous transluminal coronary angioplasty at initial angiography, patency was sustained at the second angiogram.

Journal of Cardiology 52 (1995) 125-134

infarctions was 745 U/l and for inferior infarctions 381 U/l. 3.5. Recurrent &hernia electrocardiography

Recurrent chest pain was reported by 10 patients between the initial and second angiogram, and in seven other patients between the second angiogram and discharge. In 13 of these patients the chest pain was considered to be of ischemic nature by the attending physician. In two patients symptoms were managed medically and in three, coronary bypass surgery was performed after 4,40 and 35 days, respectively. In live patients, percutaneous transluminal coronary angioplasty was performed at the time of the angiography, and in three other patients percutaneous transluminal coronary angioplasty was performed at a later stage, between 5 and 11 days after allocation. In one other patient percutaneous transluminal coronary angioplasty was performed because of STsegmentdepression during a predischarge exercise test. All patients with recurrent chest pain were eventually discharged in good condition. None showed secondary enzyme rise indicative for reinfarction. Continuous vector-electrocardiographic recording were adequatefor analysis in 47 patients. Early ST segment variability, defined as one or more episodesof increase of ST-VM during the first 4 h APTT

3.4. Infarct size

Infarct size was estimated as the quantity of (Yhydroxybutyrate dehydrogenase released by the heart per litre plasma in 72 h (a-hydroxybutyrate dehydrogenase-Q72). Complete series of nonhemolytic blood samples for determination of infarct size were available in 45 patients (90%). The calculated median infarct size was 416 U/l. In four patients a-hydroxybutyrate dehydrogenase-Q72 was estimated from series of measurementsup to 48 h [3]. In one case with incomplete sampling after a cerebrovascular accident, infarct size was assumed to equal the highest measured value (worst caseimputation). Thus for the total patient population, measured or estimated, the median CXhydroxybutyrate dehydrogenase-QR for anterior

and continuous vector-

in seconds

300

200

100

.

.

(I

0

40

20 time

in hours

Fig. 3. APTT values, median, 25% and 75’Gquartiles and range before and after initiation of thrombolytic therapy, including alteplase, heparin and ridogrel.

L.R. van der Wieken et al. /International

of recording, was observed in 27 patients (60%). In nine patients (19O/,)new ST-changes indicating myocardial ischemia were observed between 4 and 24 h after allocation. 3.6. Hemostatic values and bleeding complications Activated partial thromboplastic time values after initiation of therapy are shown in Fig. 3. According to previously developed criteria [33], an adequate level of anti-coagulation was maintained in 20 patients. The ridogrel levels at 3 h were 4.4 pg/ml (range 0.2-2.6). Twenty-three bleeding episodes were observed in 18 patients. One patient suffered an intracerebral hemorrhage during angiography, causing death 21 days later. In 14 patients large hematomas (> 5 cm diameter) were found in the groin, related to catheterisation, and three patients had an hematoma at another site. Blood transfusions were given in two patients. In one patient hematemesissubsequent to violent vomiting developed 5 h after allocation and prompted the clinician to Table 4 Results of continuous vector-electrocardiography Study

Number of patients Mean (S.D.) maximum ST-VM during first 4h Early ST variability ( > 2 episodes) Recurrent ischemia 4-24 h Mean (S.D.) time to ST-VM decline (mm) Mean (SD.) time to QRS-VD plateau (mitt)

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discontinue heparin and ridogrel and to transfuse blood. A Mallory-Weiss laceration was found and treated. In three others transient macroscopic hematuria was detected. Surgery for a bleeding complication was not necessaryin any of the patients. 4. Discussion

Ridogrel is an inhibitor of thromboxane-A2 synthetase and the TXA2/prostaglandin endoperoxide receptor blocker. This results in inhibition of platelet aggregation and vasodilation [ 19,201. Theoretically, combination of thrombolytic therapy with ridogrel might facilitate thrombolysis, enhancing early coronary patency, and might prevent rethrombosis and reocclusion. Although the current study is not conclusive since it had no control group and since the number of patients was limited, there is no evidence for a more rapid thrombolysis than with alteplase alone. On the other hand, the data suggest that recurrent ischemia might indeed be reduced by ridogrel.

in 47 patients TEAHAT

Ridogrel

GISSI-2 + Intern.

Ridogrel + alteplase

SK

ASA + alteplase

ASA + alteplase

Placebo

47 348 (225)

77 351 (220)

73 319 (226)

56 252 (183)

47 310 (192)

60%

67%

49%

34%

34%

19%

41%

37%

138 (109)

170 (105)

147 (102)

155 (116)

224 (143)

138 (99)

177 (89)

147 (87)

176 (155)

307 (261)

-

Data of the current study (left column) are compared with data from 150 patients treated with streptokinase (SK) or alteplase in the context of the GISSI-II and International study [36] and with data from patients treated with alteplase (56) or placebo (47) in the TEAHAT study [31]. Note reduction of recurrent ischemia, between 4 and 24 h, compared with streptokinase or alteplase treatment without ridogrel (P = 0.03). In the GISSI-II and International study, all patients received aspirin 125 mg, half the patients were treated with subcutaneous heparin 2 x 12 500 IU, starting 12 h after initiation of thrombolytic therapy, while the others did not receive heparin. In the TEAHAT study patients received iv. heparin, 5000 IU bolus and continuous infusion for 3-4 days. ASA was administered within 24 h of admission. The values between brackets indicate standard deviations.

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Coronary patency at initial angiography (median time 102 min) in the current study was 86% (thrombolysis in myocardial infarction grade 2-3), which was similar to the 89% patency at 90 min, estimated in a study by the European Cooperative Study Group with the same alteplase regimen [6]. It should be realised, however, that in most other studies with similar alteplase regimens lower patency rates were observed averaging 75% [5]. Similar high patency rates (S&90%) were obtained with accelerated alteplase administration [34]. The time to reperfusion, as estimated from continuous vector-electrocardiography, was also comparable with the results of a previous study [35]. Furthermore, the time to ST-VM decline from continuous vector-electrocardiography and the time until plateau of QRS-VD were similar to those observed in two other studies with alteplase [31] (Table 4), albeit more rapid than in patients treated with placebo in TEAHAT. These observations indicate that indeed thrombolysis with alteplase is not facilitated by ridogrel. Prevention of rethrombosis by ridogrel is suggestedby the absenceof reocclusion in 39 patients with a patent vesselat initial angiography who did not undergo percutaneous transluminal coronary angioplasty. In a similarly designedstudy, reocclusion between initial and second angiography was 7% (five out of 73 patients) [37]. The antithrombotic efficacy of ridogrel is also supported by the absence of reocclusion during the rescue percutaneous transluminal coronary angioplasty procedures while rescue percutaneous transluminal coronary angioplasty failed to open the vessel in 14 out of 72 patients treated with alteplase, heparin and aspirin [6]. Recurrent ischemia during 4-24 h seemedless frequent in the current study (19%) than in patients treated with alteplase in the GISSI II and International study (37%, P = 0.03) (Table 4). This difference may reflect a beneficial effect of ridogrel, but it may also be due to the more intensive heparin regimen in the current study, compared with GISSI II. The number of episodesof new chest pain in the current study was not reduced compared with the recent European Council Study Group-6 study [3X].

Journal of Cardiology 52 (1995) 125-134

Infarct size, as estimated by cumulative CYhydroxybutyrate dehydrogenase release, in the current study was smaller (median 469 U/l) than in a recent study by the European Council Study Group [38] (661 U/l). However, it should be realised that inclusion criteria in the current study were less stringent since a larger degree of ST-segment elevation was required in the latter. Furthermore in the current study more patients were entered with inferior wall infarction (74O), while in other studies the numbers of inferior and anterior infarctions were more balanced. Nevertheless, infarct sizewas only 472 U/l in patients with inferior wall infarction, compared with 6 17 U/l in the European Council Study Group-6 when the same inclusion criteria were applied. No difference was observed in infarct size in anterior infarctions between the current study (745 U/l) compared with the European Council Study Group-6 [38] (735 U/l). A smaller infarct size in patients with inferior wall infarction in the current study could be a chance finding, but it might also indicate less infarct extension as a result of a lower incidence of rethrombosis after ridogrel compared with aspirin. Bleeding complications were observed in 18 patients (36%) including one fatal intracerebral hemorrhage. This is similar to the incidence of bleeding in another study by the European Council Study Group which included early angiography [6] (75 out of 183 patients, 41%). This suggeststhat the combination of alteplase with heparin and ridogrel has a similar safety profile as alteplase with heparin and aspirin. In conclusion, the results of this pilot study suggest that ridogrel may be a valuable adjunct to reduce recurrent ischemia after thrombolytic therapy. A larger trial comparing ridogrel with aspirin in patients treated with streptokinase has been presented recently supporting the notion that ridogrel reduces thrombotic complications after thrombolysis [39]. Accordingly further trials of ridogrel, or similar compounds, in combination with different thrombolytic agents seem warranted. Non-invasive assessmentof reperfusion and reocclusion by continuous electrocardiography and determination of infarct size from

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serum enzymesappear to be suitable methods for the evaluation of the efficacy of new thrombolytic regimens. Acknowledgment The study was supported by Janssen Research Foundation, Beerse, Belgium and Janssen Pharmaceutica B.V., Tilburg, The Netherlands. References 111Gruppo Italian0 per lo studio della streptochinasi nell’in-

farto miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 397-402. [21 ISIS-2. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17, 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; i: 349-360. [31 Van de Werf F, Arnold AER. Intravenous tissue plasminogen activator and size of infarct, left ventricular function and survival in acute myocardial infarction. Br Med J 1988; 297: 1374-1379. [41 Simoons ML, Vos J, Tijssen JGP, Vermeer F, Verheugt FWA, Krauss XH. Manger Cats V. Long-term benefit of early thrombolytic therapy in patients with acute myocardial infarction: S-year follow-up of a trial conducted by the Interuniversity Cardiology Institute of the Netherlands. J Am Co11Cardiol 1989; 14: 1609-1615. [51 Gringer CB, Califf RM, Top01 E. Thrombolytic therapy for acute myocardial infarction. A review. Drugs 1992; 44. 293-325. WI Simoons ML, Arnold AER, Betriu A et al. Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet 1988; i: 197-203. 171 Top01 EJ, Califf RM, George BS et al, and the TAM1 Study Group. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987; 317: 581-589. [sl Mitchel JRA. Clinical aspects of the arachidonic acidthromboxane pathway. Br Med Bull 1983; 39 (3): 289-295. I91 Halushka PV, Dollery CT, MacDermot J. Thromboxane and prostacyclin in disease: a review. Q J Med (New Series 1.11) 1983; 208: 461-470. WI Braden GA, Fitzgerald DJ, Knapp HR, FitzGerald GA. Increased thromboxane TXA, biossynthesis during coronary thrombosis and thrombolysis with n-3 fatty acid (FA) supplementation. Circulation (Suppl II), 1988; 78 (4): 120.

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