Editorial
Aspirin and dipyridamole in the prevention of coronary disease and coronary artery bypass graft occlusion
T
he usual pathophysiologic basis of acute myocardial infarction (AMI) is atheromatous plaque rupture, which leads to platelet aggregation and formation of an occluding coronary thrombus.' Since platelet aggregation plays an important role in the pathogenesis of coronary thrombosis, there is an expectation that antiplatelet drugs will be beneficial in the prevention of coronary disease. Several antiplatelet drugs including aspirin and dipyridamole have been evaluated by clinical studies. These studies have confirmed the efficacy of aspirin but the value of dipyridamole remains uncertain.2 Aspirin inhibits platelet function by irreversible acetylation of platelet cyclo-oxygenase, a key enzyme in the prostaglandin pathway and blocking the biosynthesis of thromboxane A2.3 Dipyridamole inhibits the phosphodiesterase enzyme in platelets, resulting in an increase in intraplatelet cyclic AMP and a decrease in platelet rea~tivity.~ Aspirin is a moderately potent platelet inhibitor and its inhibitory effect can be easily demonstrated after a single oral dose of 100 mg.3 In contrast, dipyridamole is a weak inhibitor and it is often difficult to demonstrate inhibition of platelet aggregation ex vivo in individuals who have received the usual oral doses of the drug.4 There is now good evidence that aspirin is beneficial in patients with AM1 during and beyond the acute and in patients with unstable The Second International Study of Infarct Survival (ISIS-2),5 a large randomised study involving more than 17 000 patients showed that one month of lowdose aspirin (160 mg daily), starting immediately in patients with suspected AMI, reduced vascular mortality at five weeks by 23% and non-fatal reinfarction by 50%. Patients given aspirin and streptokinase had an even lower vascular mortality (42yo) suggesting that the effects of both drugs were synergistic. The benefit of aspirin in this clinical setting may be related to the prevention of coronary reocclusion after spontaneous or streptokinase-induced thrombolysis. The benefit of antiplatelet therapy persists beyond the Short treatment period studied in ISIS-2. No less than ten trials have evaluated the long-term treatment
of antiplatelet drugs in patients with myocardial infarction (MI) (eight studied aspirin, 300-1500 mg/day with or without dipyridamole and two sulphinpyrazone).* An overview of these studiesZconcluded that the longtermed antiplatelet treatment reduced vascular mortality by 13% and non-fatal reinfarction by 31%. The outcomes of these trials were not influenced by the drug regimen (whether aspirin alone, aspirin plus dipyridamole or sulphinpyrazone) nor by the aspirin dosage. In addition, three clinical studies have found that aspirin (300-1300 mglday) reduced the risk of cardiac death and nonfatal MI by over 50% as compared with placebo.8-10 The value of aspirin in the primary prevention of MI was investigated by two large recent s t ~ d i e s .The ~.~ Physicians' Health Study in the United States6 studied more than 22 000 male physicians 40 to 84 years of age with no history of MI or stroke. T o determine whether aspirin decreased cardiovascular mortality, participants were given aspirin 325 mg every other day or placebo. The study found a 44% reduction in the risk of MI in the aspirin group but this risk reduction was apparent only among those who were 50 years of age and older. A smaller study7 which investigated about 5000 apparently healthy British male doctors who took either 500 mg of aspirin daily or placebo, revealed only a favourable trend towards a reduction in MI by aspirin. Neither studies found a significant decrease in vascular mortality in the active treatment group. A disturbing finding in both studies was a slight increase in the incidence of haemorrhagiddisabling strokes in those receiving a s p i ~ i n . ~ , ~ Dipyridamole, on the other hand, has been investigated only in secondary prevention studies of MI.".'' In the Persantin-Aspirin Reinfarction Study I (PARIS-I)," 2026 patients who survived an MI were randomised to receive dipyridamole plus aspirin, aspirin alone or placebo. There was a trend towards a reduction in coronary mortality and reinfarction in both activetreatment groups but no significant difference between the active-treatment groups in their effects on these end points. PARIS-I112 tested dipyridamole plus aspirin against placebo and found a 24% reduction in
Reprint requests to: Dr B.H. Chong, Department of Haematology, Prince of Wales Hospital, High Street, Randwick, NSW 2031, Australia. ASPIRIN AND DIPYRIDAiMOLE: CORONARY DISEASE
Aust NZ J Wed 1992; 22
645
MI in those given active treatment but no significant decrease in mortality. In these studies, there was no evidence to suggest that adding dipyridamole to aspirin was likely to offer any additional benefit. The situation appears to be slightly different with vein graft occlusion after coronary artery bypass graft (CABG) surgery. Injury to the graft is unavoidable during graft harvesting. 13,14 Platelet deposition occurs at endothelial injury sites during or immediately after surgery, and may lead to thrombus formation and early graft o c cl ~s ion.'~~'~ In animal studies, these thrombotic processes were found to contribute to subsequent intimal smooth muscle proliferation, which is associated with late graft occlusion.'4 Later, atherosclerotic process occurs causing further graft occlusion. T o achieve maximum protection, antiplatelet measures should ideally start before or as soon as possible after ~urgery.'~ This is confirmed by clinical studies which showed that antiplatelet treatment starting before or within the first day after surgery was effective in preventing graft occlusion but therapy initiated on day 3 to 5 postoperatively was universally ineffe~tive.'~ No less than 16 have evaluated the efficacy of several antiplatelet regimens, including aspirin alone and aspirin plus dipyridamole and found both regimens to be efficacious. Chesebro, for instance, showed that aspirin and dipyridamole, reduced early graft occlusion at one month from 10% in controls to 2% in treated patients and late occlusion at one year from 23% to 119'0.'~The question is whether one regimen is superior to another. There are some data from animal and clinical studies which favour slightly the use of aspirin plus dipyridamole. First, animal studies showed that in dogs treated with dipyridamole before and aspirin added after surgery, there was marked reduction of platelet deposition and thrombus formation at the site of the graft, and although dipyridamole-aspirin therapy did not completely eliminate the intimal smooth muscle proliferation, it did substantially reduce it.18 Second, unlike aspirin, dipyridamole started before surgery will not increase surgical bleedingi3ai4 or reoperation rate.I4.I9Third, although a meta-analysis of 13 trials15 suggested no difference in effects between aspirin alone and aspirin plus dipyridamole, the two regimens were not directly compared. When direct comparison was made in a large study of more than 1100 patients,16 a lower graft occlusion rate was observed in patients with aspirin plus dipyridamole than those given aspirin alone. In contrast, three smaller studies'8-20which also made the direct comparison including the study by Agnew et a1.18 (on page 665 in this issue of the Journal) revealed no difference between the two treatment regimens but this may be attributed to the small numbers of patients in these three studies. 646
Interestingly, Agnew and colleaguess found increased side-effects and patient withdrawals among patients treated with aspirin and dipyridamole and they appropriately pointed out that the possible minor beneficial effect on graft patency with this treatment regimen should be weighed against the increase in sideeffects and drug cost and the decrease in compliance. The available evidence suggests that long-term aspirin is beneficial to patients who have or unstable and to apparently healthy men over the age of 50 years for the prevention of the first MI,6 provided they do not have specific contra-indications such as poorly controlled hypertension or diabetic retinopathy. In addition, patients undergoing CABG surgery should receive aspirin for a year, starting within 24 hours postoperatively.'4~'sLow-dose aspirin (160 to 325 mg/day) seems to be as effective as high doses of the drug (975-1500 mg/day)2.*' but the latter are probably more gastrotoxic. Adding dipyridamole to aspirin appears to provide no additional protection in the prevention of coronary disease2~",12but may slightly improve graft patency after CABG surgery.16 This minor beneficial effect has to be weighed against the possible increase in side effects and decrease in compliance. l 8
B. H. CHONG, Haematologist and Associate Professor, Department of Haematology, Prince of Wales Hospital, Sydney, NSW.
References 1. Fuster V, Badmon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988; 77: 1213-20. 2. Antiplatelet Trialists Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296; 320-31. 3. Patron0 C, Ciabattoni G, Bradrignani P, ec a[. Clinical pharmacology of platelet cyclo-oxygenase inhibition. Circulation 1985; 72: 1177-84. 4. Fitzgerald GA. Dipyridamole. N Engl J Med 1987; 316: 1247-57. 5. ISIS-2 (Second International Study of Infirct Survival)Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 191, ii: 349-60. 6. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl f Med 1989; 321: 12935. 7. Pet0 R, Gray R, Collins R cr aL Random& ' nialof prophylactic daily aspirin in British male doctors. Br Mcd J 1988; 296: 313-6.
( R e j m c e r continued on page 678.)
Aust NZ J Med 1992; 22
CHONG
Aspirin and dipyridamole in the prevention of coronary disease and coronary artery bypass graft occlusion
T
he usual pathophysiologic basis of acute myocardial infarction (AMI) is atheromatous plaque rupture, which leads to platelet aggregation and formation of an occluding coronary thrombus.' Since platelet aggregation plays an important role in the pathogenesis of coronary thrombosis, there is an expectation that antiplatelet drugs will be beneficial in the prevention of coronary disease. Several antiplatelet drugs including aspirin and dipyridamole have been evaluated by clinical studies. These studies have confirmed the efficacy of aspirin but the value of dipyridamole remains uncertain.2 Aspirin inhibits platelet function by irreversible acetylation of platelet cyclo-oxygenase, a key enzyme in the prostaglandin pathway and blocking the biosynthesis of thromboxane A2.3 Dipyridamole inhibits the phosphodiesterase enzyme in platelets, resulting in an increase in intraplatelet cyclic AMP and a decrease in platelet rea~tivity.~ Aspirin is a moderately potent platelet inhibitor and its inhibitory effect can be easily demonstrated after a single oral dose of 100 mg.3 In contrast, dipyridamole is a weak inhibitor and it is often difficult to demonstrate inhibition of platelet aggregation ex vivo in individuals who have received the usual oral doses of the drug.4 There is now good evidence that aspirin is beneficial in patients with AM1 during and beyond the acute and in patients with unstable The Second International Study of Infarct Survival (ISIS-2),5 a large randomised study involving more than 17 000 patients showed that one month of lowdose aspirin (160 mg daily), starting immediately in patients with suspected AMI, reduced vascular mortality at five weeks by 23% and non-fatal reinfarction by 50%. Patients given aspirin and streptokinase had an even lower vascular mortality (42yo) suggesting that the effects of both drugs were synergistic. The benefit of aspirin in this clinical setting may be related to the prevention of coronary reocclusion after spontaneous or streptokinase-induced thrombolysis. The benefit of antiplatelet therapy persists beyond the Short treatment period studied in ISIS-2. No less than ten trials have evaluated the long-term treatment
of antiplatelet drugs in patients with myocardial infarction (MI) (eight studied aspirin, 300-1500 mg/day with or without dipyridamole and two sulphinpyrazone).* An overview of these studiesZconcluded that the longtermed antiplatelet treatment reduced vascular mortality by 13% and non-fatal reinfarction by 31%. The outcomes of these trials were not influenced by the drug regimen (whether aspirin alone, aspirin plus dipyridamole or sulphinpyrazone) nor by the aspirin dosage. In addition, three clinical studies have found that aspirin (300-1300 mglday) reduced the risk of cardiac death and nonfatal MI by over 50% as compared with placebo.8-10 The value of aspirin in the primary prevention of MI was investigated by two large recent s t ~ d i e s .The ~.~ Physicians' Health Study in the United States6 studied more than 22 000 male physicians 40 to 84 years of age with no history of MI or stroke. T o determine whether aspirin decreased cardiovascular mortality, participants were given aspirin 325 mg every other day or placebo. The study found a 44% reduction in the risk of MI in the aspirin group but this risk reduction was apparent only among those who were 50 years of age and older. A smaller study7 which investigated about 5000 apparently healthy British male doctors who took either 500 mg of aspirin daily or placebo, revealed only a favourable trend towards a reduction in MI by aspirin. Neither studies found a significant decrease in vascular mortality in the active treatment group. A disturbing finding in both studies was a slight increase in the incidence of haemorrhagiddisabling strokes in those receiving a s p i ~ i n . ~ , ~ Dipyridamole, on the other hand, has been investigated only in secondary prevention studies of MI.".'' In the Persantin-Aspirin Reinfarction Study I (PARIS-I)," 2026 patients who survived an MI were randomised to receive dipyridamole plus aspirin, aspirin alone or placebo. There was a trend towards a reduction in coronary mortality and reinfarction in both activetreatment groups but no significant difference between the active-treatment groups in their effects on these end points. PARIS-I112 tested dipyridamole plus aspirin against placebo and found a 24% reduction in
Reprint requests to: Dr B.H. Chong, Department of Haematology, Prince of Wales Hospital, High Street, Randwick, NSW 2031, Australia. ASPIRIN AND DIPYRIDAiMOLE: CORONARY DISEASE
Aust NZ J Wed 1992; 22
645
MI in those given active treatment but no significant decrease in mortality. In these studies, there was no evidence to suggest that adding dipyridamole to aspirin was likely to offer any additional benefit. The situation appears to be slightly different with vein graft occlusion after coronary artery bypass graft (CABG) surgery. Injury to the graft is unavoidable during graft harvesting. 13,14 Platelet deposition occurs at endothelial injury sites during or immediately after surgery, and may lead to thrombus formation and early graft o c cl ~s ion.'~~'~ In animal studies, these thrombotic processes were found to contribute to subsequent intimal smooth muscle proliferation, which is associated with late graft occlusion.'4 Later, atherosclerotic process occurs causing further graft occlusion. T o achieve maximum protection, antiplatelet measures should ideally start before or as soon as possible after ~urgery.'~ This is confirmed by clinical studies which showed that antiplatelet treatment starting before or within the first day after surgery was effective in preventing graft occlusion but therapy initiated on day 3 to 5 postoperatively was universally ineffe~tive.'~ No less than 16 have evaluated the efficacy of several antiplatelet regimens, including aspirin alone and aspirin plus dipyridamole and found both regimens to be efficacious. Chesebro, for instance, showed that aspirin and dipyridamole, reduced early graft occlusion at one month from 10% in controls to 2% in treated patients and late occlusion at one year from 23% to 119'0.'~The question is whether one regimen is superior to another. There are some data from animal and clinical studies which favour slightly the use of aspirin plus dipyridamole. First, animal studies showed that in dogs treated with dipyridamole before and aspirin added after surgery, there was marked reduction of platelet deposition and thrombus formation at the site of the graft, and although dipyridamole-aspirin therapy did not completely eliminate the intimal smooth muscle proliferation, it did substantially reduce it.18 Second, unlike aspirin, dipyridamole started before surgery will not increase surgical bleedingi3ai4 or reoperation rate.I4.I9Third, although a meta-analysis of 13 trials15 suggested no difference in effects between aspirin alone and aspirin plus dipyridamole, the two regimens were not directly compared. When direct comparison was made in a large study of more than 1100 patients,16 a lower graft occlusion rate was observed in patients with aspirin plus dipyridamole than those given aspirin alone. In contrast, three smaller studies'8-20which also made the direct comparison including the study by Agnew et a1.18 (on page 665 in this issue of the Journal) revealed no difference between the two treatment regimens but this may be attributed to the small numbers of patients in these three studies. 646
Interestingly, Agnew and colleaguess found increased side-effects and patient withdrawals among patients treated with aspirin and dipyridamole and they appropriately pointed out that the possible minor beneficial effect on graft patency with this treatment regimen should be weighed against the increase in sideeffects and drug cost and the decrease in compliance. The available evidence suggests that long-term aspirin is beneficial to patients who have or unstable and to apparently healthy men over the age of 50 years for the prevention of the first MI,6 provided they do not have specific contra-indications such as poorly controlled hypertension or diabetic retinopathy. In addition, patients undergoing CABG surgery should receive aspirin for a year, starting within 24 hours postoperatively.'4~'sLow-dose aspirin (160 to 325 mg/day) seems to be as effective as high doses of the drug (975-1500 mg/day)2.*' but the latter are probably more gastrotoxic. Adding dipyridamole to aspirin appears to provide no additional protection in the prevention of coronary disease2~",12but may slightly improve graft patency after CABG surgery.16 This minor beneficial effect has to be weighed against the possible increase in side effects and decrease in compliance. l 8
B. H. CHONG, Haematologist and Associate Professor, Department of Haematology, Prince of Wales Hospital, Sydney, NSW.
References 1. Fuster V, Badmon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988; 77: 1213-20. 2. Antiplatelet Trialists Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296; 320-31. 3. Patron0 C, Ciabattoni G, Bradrignani P, ec a[. Clinical pharmacology of platelet cyclo-oxygenase inhibition. Circulation 1985; 72: 1177-84. 4. Fitzgerald GA. Dipyridamole. N Engl J Med 1987; 316: 1247-57. 5. ISIS-2 (Second International Study of Infirct Survival)Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 191, ii: 349-60. 6. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl f Med 1989; 321: 12935. 7. Pet0 R, Gray R, Collins R cr aL Random& ' nialof prophylactic daily aspirin in British male doctors. Br Mcd J 1988; 296: 313-6.
( R e j m c e r continued on page 678.)
Aust NZ J Med 1992; 22
CHONG
