Chronic-intermittent urokinase therapy in refractory angina pectoris

Fibrinolysis(1995) 9, Suppl 1 : 121-125 © 1995PearsonProfessionalLtd

Chronic-intermittent Urokinase Therapy in Refractory Angina Pectoris

F.-C. Schoebel*, M. Leschke, D. Stein, M. Heins, K. Pels, T.W. Jax, B.-E. Strauer

S U M M A R Y. Patients with coronary artery disease and severe angina pectoris refractory to conventional medical treatment (beta-blockers, nitrates, calcium antagonists) and without the option for invasive revascularization procedures, present an increasing clinical problem. For these patients, chronic-intermittent urokinase therapy has been developed as a combined rheological and thrombolytie approach to the improvement of myocardial perfusion. In chronic-intermittent urokinase therapy 500,000 IU of urokinase are applied 3 times a week over a period of 12 weeks as an intravenous bolus injection. The target fibrinogen level, which is the major determinant of rheological blood properties (plasma viscosity, red blood cell aggregation) in microcirculation should range between 200 and 250 mg/dl. Reductions of fibrinogen levels amount to an average of about 35 %, with subsequent reductions of plasma viscosity (approx. -7%) and red blood cell aggregation (approx. -18%). These changes are accompanied by significant reductions of clinical symptoms (anginal events/week) by approximately 75% from initially 23 + 12 events/week; the clinical therapeutic effect is achieved after 2-4 weeks of treatment. Apart from the clinical improvements, objective signs of myocardial ischemia during ergometric exercise testing - such as 'average negative ST-segment deviation', 'endpoint at termination of exercise' and 'exercise time to angina pectoris and/or to negative ST-segment deviation > 0.1mV' - change favorably after treatment. A dose-response study which compared the application of 3 x 50,000 IU/week (n = 49) with 3 x 500,000 IU/week (n = 49) in patients with refractory angina pectoris could demonstrate a beneficial dose-dependent clinical effect for the higher dosage, which seems to be closely related to the reductions of the fibrinogen levels. There was no cumulation of undesirable side effects like an increase of coronary isehemic events and bleeding complications in the high-dose group. After termination of therapy with 3 x 500,000 1U urokinase/week (n = 121), the therapeutic effect (reduction of anginal events > 66%/week) lasted for 13.9 + 8.6 months during a follow up period of 19.3 + 10 months. Conclusion: Chronic-intermittent urokinase therapy in a dosage of 3 x 500,000 IU/week over a period of 12 weeks represents an effective antiischemic and antianginal approach in patients with refractory angina pectoris and end-stage coronary artery disease.

The therapeutic options for the management of angina pectoris in patients with coronary artery disease (CAD) have increased and improved impressively over the last 20 years. Apart from the three mainstays of medical ther-

apy (nitrates, beta blockers and calcium antagonists) invasive procedures such as coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) have been established as effective means of reducing myocardial ischemia and hence anginal symptoms. Nevertheless, clinicians continue to be confronted with patients who suffer from severe symptomatic coronary artery disease and are refractory both to conventional medical therapy and to the established revascularization procedures. As the life expectancy of patients with coronary artery disease is increasing - due to improved secondary prevention of cardiovascular death (aspirin, beta blockers, angiotensin converting enzyme inhibitors, thrombolytic therapy and invasive revascular-

F r a n k - C h r i s Schoebel MD, Matthias Leschke MID, Dirk Stein, Klaus Pels MD, T h o m a s Walter Jax, Bodo-Eckehard Strauer MD, Heinrich Heine Universit~it Diisseldorf, Medizinische Klinik und Poliklinik B, Kiinik fiir Kardiologie, Pneumoiogie und Angiologie, Michael Heins MD, Institut fiir Klinische Chemie und Laboratoriumsdiagnostik, Moorenstrasse 5, 40225 Diisseldorf, Germany. *Recipient of the Ernst Deutsch Poster Award - Clinical Sciences, Update in Thrombolysis, Vienna 1994. This report was supported by a federal grant from the Deutsche Forschnngsgemeinschaft, Sonderforschungsbereich 242: Koronare Herzkrankheit - Pr[ivention und Therapie akuter Komplikationen.

121

122 UrokinaseTherapy in Refractory Angina Pectoris ization procedures) - we can also expect to see an increase in the prevalence of patients with refractory angina pectoris. For these patients 'chronic-intermittent urokinase therapy' was developed as a combined rheological and thrombolytic therapy for the improvement of myocardial ischemia. 1.2,3 Table 1 Clinical characteristics of patients with refractory angina pectoris (n = 98)6 Age (years) Male (%)

Patient history Myocardial infarction (%) CABG (%) Angina class IV (%) Frequency of angina pectoris (events/week) Intake of nitrate capsules (capsules/week) Medication Nitrates (%) Beta-blockers (%) Calcium antagonists (%) Triple combination therapy (%) Rheological parameters Fibrinogen (mg/dl) Plasma viscosity (mPas) Red blood cell aggregation (units) Data frominvasiveprocedures Coronary triple vessels disease (%) Number of bypasses Number of bypasses occluded Left ventricular ejection fraction (%) Left ventricular end diastolic pressure (ram Hg)

62 +_9 91 89 70 59 23.2 + 10.8 13.9 + 9.6 100 71 95 67 359 + 73 1.39 + 0.07 14.7 + 2,9 99 3.3 + 1.0 1.6 + 1.0 47 + 17 17.7 + 6.7

Definition of Refractory Angina pectoris and Patient Characteristics Refractory angina pectoris in patients with coronary artery disease may be diagnosed, when a patient suffers from severe angina pectoris class III or IV according to the classification of the Canadian Cardiovascular Society 4 despite maximally tolerated conventional antianginal medical combination therapy (nitrates, beta-blockers, calcium antagonists). 5 Patients who suffer from angina class IV are severely impaired in their regular physical and social activities, angina may occur at rest. Even though most patients receive an antianginal triple combination therapy (Table 1), this is not a necessary precondition for the diagnosis of refractory angina pectoris because some patients may only tolerate two drugs due to undesirable side effects (hypotension, symptomatic bradycardia, subjective discomfort). As mandatory precondition an option for an invasive revascularization procedure (PTCA, CABG) has to be ruled out by an experienced team of cardiologists and cardiac surgeons based on a recent coronary angiogram in order not to withhold an established form of therapy from the patients.

Patients selected according to these guidelines are characterized by coronary triple vessel disease with severe, successive multiple stenoses and total occlusions of coronary conductance vessels or coronary bypass grafts in almost all cases (Table 1). In contrast to severe coronary insufficiency there do remain large areas of viable myocardium as reflected by an only slightly to moderately impaired left ventricular ejection fraction at rest of 47 + 17% (normal: > 60%). 6 In addition, fibrinogen levels according to the Clauss method 7 and dependent rheological parameters, like plasma viscosity and red blood cell aggregation, are elevated (Table 1) in respect to normal subjects (fibrinogen: 227 + 50 mg/dl, n = 16; plasma viscosity: 1.24 + 0.07 mPas, n = 34; red blood cell aggregation: 9.6 + 3.2 units, n = 28) 8 as well as in comparison to patients with coronary artery disease and non-refractory angina pectoris (fibrinogen: 295 + 69 mg/dl, n = 44; plasma viscosity: 1.33 + 0.08 mPas, n = 78; red blood cell aggregation: 13.1 _+ 3.1 units, n = 42). 8 These rheological abnormalities indicate that patients with refractory angina are, in addition to severe coronary insufficiency, at the level of the coronary conductance vessels characterized by disturbances of microcirculatory blood flow properties.

Chronic Intermittent Urokinase Therapy

Therapeutic Principles and Mechanisms Chronic-intermittent urokinase therapy is applied in a low dosage of 500,000 IU 3 times a week, over a period of 12 weeks, as an intravenous bolus injection. According to the pilot study (n = 24), 3 the application of urokinase leads to marked reductions of fibrinogen levels by about 35% with subsequent improvements of rheological blood properties (reduction of plasma viscosity: -7%; reduction of red blood cell aggregation: -18%) in patients with refractory angina pectoris. Fibrinogen target levels, which are reached after two to four weeks of therapy, should range between 200 and 250 mg/dl; adjustments of dosage of urokinase may be necessary by an increase or decrease of the injections per week. Apart from these clinical symptoms, factors of blood coagulation (fibrinogen, thromboplastin time) should be monitored every other week for unwanted side effects. The improvement of rheological blood properties with a resulting increase of coronary microcirculation can be assumed to be the primary therapeutic mechanism. Under conditions of non-impaired epicardial blood flow, the flow limiting effect of blood viscosity in the microcirculation, which is determined mainly by plasma 9IF viscosity and red blood cell aggregation, - can be disregarded. However, in the poststenotic microcirculation of severe and multiple successive stenoses or occluded vessels, blood viscosity is a flow limiting factor and may therefore play a critical role in oxygen delivery to the 12 13 ischemic myocardium. ' Under these particular conditions, at extremely low shear rates and at an almost zero flow, 14 it is predominantly fibrinogen which, due to its

Update in Thrombolysis 1994

123

Table 2 Dose-response study: fibrinogen and theological parameters 6

Treatment period Fibrinogen (mg/dl) Plasma viscosity (mPas) Red blood cell aggregation (U)

3 x 50,000 IU urokinase/week (n = 43)

3 x 500,000 IU urokinase/week (n = 46)

Prior

Post

Prior

Post

351 + 79 1.38 ± 0.09 15.0 _+3.0

333 ± 63 n.s. 1.37 -+0.08 n.s. 14.05 ± 3.2 n.s.

369 -+ 66 1.40 _+0.05 14.8 -+ 2.7

242 -+40*** ! .31 -+0.05*** 11.7 -+ 2.3 ***

*p < 0.05. **p < 0.01, *p < 0.001

Dose-dependency of Clinical and Antiischemic Effectiveness

high molecular weight and therefore its effect on red blood cell aggregation, leads to an exponential increase in blood viscosity (i.e. structural blood viscosity). Thrombi are considered to play a major role in the progression o f corona5~ artery disease in clinically stable coronary syndromes and can be o f flow-limiting relevance in the epicardial conductance vessels, 15 as well as in the coronary microcirculation. 16 Therefore, lysis of thrombotic material in critically stenosed coronary arteries may lead to an improvement of myocardial blood flow. Apart from the fibrinogenolytic effect, the thrombolytic properties o f this therapeutic regimen therefore have to be considered which is indicated by a decrease of plasminogen activity by 7-19%. 3

In order to validate this therapeutic approach further, a dose-response study was conducted, which compared the application of 3 x 50,000 IU urokinase (group A, n = 49) with 3 x 500,000 IU urokinase ~ r o u p B, n = 49) per week over a period of 12 weeks. The group which received the higher dosage (group B) clearly demonstrated a more favorable effect. Fibrinogen levels were reduced by 33% in group B in comparison to 18% in group A (Table 2). These changes were accompanied by improvements of rheological blood properties (Table 2) and clinical symptoms (Table 3). Even though clinical symp-

Table 3 Dose-response study: subjective parameters of myocardial ischemia6

Treatment period Angina pectoris (events/week) Intake of nitrate capsules (capsules/week) Responders (reduction of angina pectoris > 66%) (%) Patients free of symptoms (%)

3 x 50,000 IU urokinase/week (n = 43)

3 x 500,000 IU urokinase/week (n = 46)

Prior

Post

Prior

Post

21.9-+9.8 13.1±7.9

15.8-+ 10.0" 8.9+6.1

24.2 -+ 11.7 14.1+11.1

7.1 -+7.1"** 2.3 + 3.4**

21

70**

7

17"

*p < 0.05, **p < 0.01. *p < 0.001 Table 4 Dose-response study: objective parameters of myocardial ischemia 6 3 x 50,000 IU urokinase/week Treatment period Maximal stress capacity (Watt x s x 0.01) Maximal rate pressure product (mm Hg x min -l x 0.01) Endpoint 'angina pectoris' Endpoint 'exhaustion' Endpoint 'negative STsegment deviation > 0.03 mV' Average ST-segment deviation Time to 'ST-segment deviation 0. I mV' (s) Time to 'angina pectoris' (s) *p < 0.05, **p < 0.01, *p < 0.001

3 x 500,000 IU urokinase/week

Prior

Post

n

20.82 -+ 11.32

21.61 + 11.57

43

166 + 39

176+49

43

36 6 1 0.15 -+0.13 308 + 117

0.14-+0.12 300_+ 112

361 + 119

363-+115

Prior

Post

20.20+ 12.15 27.93+ 12.66"

n 46

169 + 43

173 + 43

35 7

32 13

14"* 32**

1

1

0

36 29

0.15+0.12 288 + 89

0.11-+0.09"* 371 + 88*

38 35

35

351-+ 131

439+ 131"

14

46

124 UrokinaseTherapy in RefractoryAngina Pectoris toms improved in both groups significantly, changes in group A may have to be attributed to a possible placebo effect, which ranges between 35 and 40% in antianginal trials. 17"18In group B, 70% of the patients were regarded as positive responders (reduction of anginal events by > 66% events/week), while this was only true for 21% of the patients in group A. Exercise studies performed before and after treatment showed significant reductions of objective parameters of myocardial ischemia in group B (Table 4). As the improvements in the objective parameters of stress induced myocardial ischemia were not accompanied by a significant increase in myocardial oxygen demand (rate-pressure product) these changes have to be attributed to an increase in oxygen supply and not to a peripheral training effect.

Side Effects and Long Term Follow Up As chronic intermittent urokinase therapy is a new therapeutic approach, side effects reward special attention. Data from the dose-response study 6 showed a drop-out rate of 12% in group A (increase of clinical symptoms > 66% events/week: three patients; myocardial infarction: two patients; drop out for no specific reason: one patient) in contrast to only 6% in group B (increase of clinical symptoms > 66% events/week: one patient; myocardial infarction: one patient; gastro-intestinal bleeding: one patient). This indicates that the application of 3 x 500,000 IU urokinase per week over a period of 12 weeks not only leads to clinical and objective improvements of myocardial ischemia, but may also have a protective effect in regard to the incidence of acute ischemic events (unstable angina, myocardial infarction). Bleeding complications are hazards which always have to be taken into consideration even though biologically relevant reductions of coagulation factors including fibrinogen were not noted. Careful assessment of patient history, low-dosage aspirin therapy, in cases necessary change from aspirin to ticlopidin as anti-platelet agent and patient monitoring every other week during the treatment period should prevent major side effects. So far 121 patients have been treated with a regimen of 3 x 500,000 IU urokinase per week over 3 months. 19 During the mean follow up of 19.3 + 10 months, a marked long term effect could be noted as the reduction of anginal symptoms > 66% events/week lasted for an average of 13.9 + 8.6 months. 35% of the patients suffered a relapse of refractory angina pectoris. 28% of the patients were treated with a second cycle of chronic intermittent urokinase therapy. Three patients underwent either high-risk PTCA or high-risk CABG for progression of coronary artery disease in vein grafts or left main disease. Three patients received heart transplant.

COMMENT The data presented provide conclusive evidence for a favorable effect of chronic-intermittent urokinase therapy on myocardial ischemia and angina pectoris in patients

with refractory angina pectoris in end-stage coronary artery disease. A therapeutic regimen of 3 x 500,000 IU urokinase per week over a period of 12 weeks produces significant reductions of clinical symptoms after two weeks and a remarkable clinical long-term effect at least up to 12 weeks after cessation of therapy. It can be assumed that the favorable therapeutic effects are due primarily to the improvement in rheologicai blood properties resulting from decreased fibrinogen levels. The impact of rheologicai parameters on poststenotic coronary blood flow is supported by clinical evidence from rheological investigations following use of high-dose thrombolysis in acute myocardial infarction,2°-23 which demonstrated improvements of rheological blood properties as a result of the fibrinogenlowering effect of thrombolytic agents such as streptokinase. This offers one explanation for the beneficial effect on mortality after late initiation of thrombolytic treatment (6 h after the onset of myocardial infarction),24-27 which would appear to be incompatible with salvage of the myocardium jeopardized by the original coronary occlusion. Further clinical evidence for the relevance of rheological blood properties in myocardial ischemia and clinical symptoms can be derived from other studies which result in the reduction of fibrinogen like medical therapy with fibrates (reductions by about 8%), 28 heparin-induced extracorporal LDL-cholesterol precipitation (HELP) (reductions by 50%) 29 and low-molecular weight heparin (reductions by 14%), 30 all of which have not been tested in refractory angina pectoris so far. Two recent studies 3°'31 have shown the beneficial effect of daily administration of low-molecular weight heparin as an antithrombotic intervention in patients with stable angina pectoris; both the frequency of clinical symptoms per day and the exercise time to angina pectoris decreased significantly. Therefore, the thrombolytic potential of urokinase even when administered in low doses must also be considered as a further therapeutic mechanism. In contrast to investigations on thrombolysis in unstable angina, which demonstrated a cumulation of side effects including ischemic myocardial events 32 in the treatment groups due to a variety of probable mechanisms such as activation of platelets, increased thrombin activity and exposure of thrombogenic plaques, 33 the data presented here do not suggest an increase in symptoms of myocardial ischemia. This may be attributed to the daily oral administration of aspirin in all patients, the low dosage of urokinase chosen and the fact that refractory angina pectoris represents a rather stable coronary syndrome in contrast to unstable angina, which is characterized by a procoagulant state. 34 The anti-ischemic and anti-anginal effectiveness of chronic-intermittent urokinase therapy in addition to maximal conventional medical therapy implies that other determinants of myocardial ischemia gain relevance in this critical situation for myocardial perfusion apart from the established therapeutic approaches, which mainly influence oxygen supply at the level of the epicardial coronary arteries or modify myocardial oxygen demand. This circumstance stresses the importance of coronary

Update in Thrombolysis 1994

microcirculation for myocardial perfusion in severe coronary artery disease, as it has been emphasized previously with regard to hypertensive heart disease, 35'36 and marks refractory angina pectoris in end-stage coronary artery dtsease as a distinct coronary syndrome characterized by coronary microcirculatory disturbances. In conclusion, chronic-intermittent urokinase therapy is a completely novel approach to the improvement of myocardial ischemia in this highly symptomatic subset of patients and can be regarded as a safe and effective form of treatment for patients with end-stage coronary artery disease and refractory angina pectoris. •

•

•

5

ACKNOWLEDGEMENTS We thank Sabine Meyer for the preparation of the manuscript.

REFERENCES 1. Ehrly AM. Schenk JF. Systemisch niedrig dosierte Langzeit-Urokinasetherapie bei schwerster Angina pectoris. Grundlagen und erste Ergebnisse. In : Strauer BE, Ehrly AM, Leschke M, eds., Fortschritte in der kardiovaskulfiren Rheologie. Miinchen: Mtinchner Wissenschaftliche Publikationen 1987; 35-38. 2. Leschke M, H6ffken H, Vogt M, Motz W, Strauer BE. Intermittent urokinase therapy as a new strategy concept in untractable angina pectoris. J Am Coil Cardiol 1989; 13: 16A (Abstract). 3. Leschke M, H6ffken H, Motz W, Blanke H, Schoebel FC, Strauer BE. Chronisch-intermittierende Urokinasetherapie bei therapierefrakt~irerAngina pectoris. Dtsch Med Wschr 1992; 117: 81-87. 4. Campeau L. Grading of angina pectoris. Circulation 1976; 54: 522-523. 5. Schoebel FC, Leschke M, Straner BE. Therapierefrakt~ireAngina pectoris - pathophysiologische Grundlagen und alternative Therapieansfitze bei der koronaren Herzkrankheit. Dtsch Med Wschr 1995; 120: 301-307. 6. Leschke M, Schoebel FC, Mecklenbeck W, Strauer BE. Chronic-intermittent urokinase therapy in end-stage coronary artery disease and refractory angina pectoris. 1995; Submitted. 7. Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-241. 8. Leschke M, Blanke H, Stellwaag M, Motz W, Strauer BE. Hyperfibrinogenfimie und pathologische Plasmaviskositfit. Dtsch Med Wschr 1988; 113: 1175-1181. 9. Schmid-Sch6nbein H. Interaction of vasomotion and blood rheology in hemodynamics. In: Lowe GDO, Barbend JC, Forbes CD. eds. Clinical aspects of blood viscosity and cell deformability. Berlin: Springer 1981: 49-65. 10. Chien S. Physiological and pathophysiological significance of hemorheology. In: Chien S, Dormandy J, Ernst E, Mattrai A, eds, Clinical hemorheology. Dordrecht: Martinus Nijhoff Publishers 1987; 125-160. I 1. Mattrai A, Whittington RB, Skalak R. Biophysics in clinical hemorheology. In: Chien S, Dormandy J, Ernst E, Mattrai A, eds. Clinical hemorheology. Dordrecht: Martinus Nijhoff Publishers 1987: 9-65. 12. Gordon RJ, Snyder GK, Tritel H, Taylor WJ. Potential significance of plasma viscosity and hematocfit variations in myocardial ischemia. Am Heart J 1974: 87:175-182. 13. Most AS, Rucco NA, Gerwitz H. Effect of a reduction of blood viscosity on maximal oxygen delivery distal to a moderate stenosis. Circulation 1986; 74: 1085-1092. 14. Jan K-M, Chien S, Bigger JT. Observations on blood viscosity changes after acute myocardial infarction. Circulation 1975; 51: 1079-1084. 15. Fuster V, Badimon L, Badimon J, Chesebro J. The pathogenesis of

125

coronary artery disease and the acute coronary syndromes (First of two parts). N Engl J Med 1992; 326: 242-250. 16. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death: Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in vascular occlusion. Circulation 1985; 71 : 699-708. 17. Benson H, McCallie Jr DP. Angina pectoris and the placebo effect. N Engl J Med 1979; 300: 1424-1429. 18. Parisi AF, Strauss WE, Mclntyre KM, Sasahara AA. Consideration in evaluating new antianginal drugs. Circulation 1982; 65 Suppl. 1: 38-42. 19. Leschke M, Schoebel FC, Strauer BE. Long-term follow up in chronic-intermittent urokinase therapy in patients with refractory angina pectoris. Ann Hematol 1994; 69 Suppl II: $67. 20. Jan K-M, Reinhardt W, Chien S et al. Altered rheological properties of blood following administration of tissue plasminogen activator and streptokinase in patients with acute myocardial infarction. Circulation 1985; 72 Suppl. III: 417 (Abstract). 21. Moriarity AJ, Hughes R, Nelson RD, Balnave K. Streptokinase and reduced plasma viscosity. A second benefit. Eur J Haematol 1988; 41: 25-36. 22. Hoffmann JJML. Blood viscosity and platelet function in thrombolytic therapy of acute myocardial infarction. Eur Heart J 1990; 11 Suppl. F: 29-35. 23. Arntz HR, Perchalla G, Roll D, Heitz J, Schfifer J-H, SchrOder R. Blood rheology in acute myocardial infarction: effect of high-dose i.v. streptokinase compared to placebo. Eur Heart J 1992; 13: 275-280. 24. YusufS, Collins R, Peto R et al. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side effects from 33 randomised controlled trials. Eur Heart J 1985; 6: 556-585. 25. Aims Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; 1: 545-549. 26. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187cases of suspected myocardial infarction: ISIS-2. Lancet 1988; 2: 349-360. 27. Chamberlain DA. Unanswered questions in thrombolysis. Am J Cardiol 1989; 63: 34A-40A. 28. Leschke M, HOffken H, Schmidtsdofff A et al. Einflu~ von Fenofibrat auf Fibrinogenkonzentration und Blutfluidit~it. Dtsch Med Wschr 1989; 114: 939-944. 29. Szymanski D, Schoebel FC, Kleophas W, Schottenfeld Y, Leschke M, Strauer BE. Die Rekoronarangiographie bei Patienten mit familifirer Hypercholesterin~nie unter HELP-Therapie: Klinische Ergebnisse und Therapieverlauf. In: Landgraf H, Jung F, Ehrly AM, eds. Klinische Mikrozirkalation. Berlin: Blackwell Wissenschafi 1993; 1-7. 30. Melandri G, Semprini F, Cervi V et al. Benefit of adding low molecular weight heparin to the conventional treatment of stable angina pectoris: a double-blind, randomized, placebo-controlled trial. Circulation 1993; 88: 2517-2523. 31. Quyyumi AA, Diodati JG, Lakatos EE, Bonow RO, Epstein SE. Angiogenic effects of low molecular weight heparin in patients with stable coronary artery disease: a pilot study. J Am Coil Cardiol 1993; 22: 635-641. 32. Theroux P, Lidon RM. Unstable angina: pathogenesis, diagnosis and treatment. Curr Prob Cardiol 1993; 17: 157-231. 33. Salvo T di, Fuster V. Antithrombotic therapy in coronary artery disease. Curt Opin Lipidol 1994; 5: 290-304, 34. Fuster V, Badimnn L, Badimon J, Chesebro J. The pathogenesis of coronary artery disease and the acute coronary syndromes (Second of two parts). N Engl J Med 1992; 326: 310-318. 35. Leschke M, Vogt M, Motz W, Strauer BE. Blood rheology as a contributing factor in reduced coronary reserve in systemic hypertension. Am J Cardiol 1990; 65: 56G-59G. 36. Strauer BE. The significance of eorunary reserve in clinical heart disease. J Am Coll Cardiol 1990; 15: 775-783.