Continuation Of Aspirin Research Articles

Prevention of Premature Discontinuation of Dual Antiplatelet Therapy in Patients With Coronary Artery Stents

Dual antiplatelet therapy with aspirin and a thienopyridine has been shown to reduce cardiac events after coronary stenting. However, many patients and healthcare providers prematurely discontinue dual antiplatelet therapy, which greatly increases the risk of stent thrombosis, myocardial infarction, and death. This advisory stresses the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent and educating the patient and healthcare providers about hazards of premature discontinuation. It also recommends postponing elective surgery for 1 year, and if surgery cannot be deferred, considering the continuation of aspirin during the perioperative period in high-risk patients with drug-eluting stents.

Aspirin Resistance or Variable Response or Both?

Numerous clinical trials have demonstrated that aspirin is effective in secondary prevention and in high-risk primary prevention of adverse cardiovascular events. However, a constellation of clinical and laboratory evidence exists that demonstrates diminished or absent response to aspirin in some patients. This has led to the concept of "aspirin resistance," which is a poorly defined, somewhat misleading term. The mechanism for aspirin resistance has not been fully established, but it is almost certainly due to a combination of clinical, biological, and genetic properties affecting platelet function. There are no criteria for distinguishing true resistance from treatment failure, and there is no consensus on whether the definition of aspirin resistance should be based on clinical outcomes, laboratory evidence, or both. Studies in large populations are needed to define antiplatelet resistance using consistent and reproducible assays and correlate the measurements with clinical outcomes. One such prospective randomized trial is completed, and 2 others are under way: the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial compared clopidogrel and aspirin with placebo and aspirin for high-risk primary or secondary prevention, and the Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial (ASCET) is evaluating whether switching to clopidogrel will be superior to continued aspirin therapy in improving clinical outcomes in aspirin-resistant patients with angiographically documented coronary artery disease. The Research Evaluation to Study Individuals Who Show Thromboxane or P2Y(12) Receptor Resistance (RESISTOR) trial is investigating whether modifying antiplatelet regimens could prevent myonecrosis after percutaneous coronary intervention in patients with aspirin and clopidogrel resistance.

Low‐dose aspirin for secondary cardiovascular prevention – cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation – review and meta‐analysis

Low-dose aspirin given for secondary prevention of cardiovascular disease is frequently withdrawn prior to surgical or diagnostic procedures to reduce bleeding complications. This may expose patients to increased cardiovascular morbidity and mortality. Aim of the study was to review and quantify cardiovascular risks because of periprocedural aspirin withdrawal and bleeding risks with the continuation of aspirin. We screened MEDLINE (January 1970-October 2004) with additional manual cross-referencing for clinical studies, surveys on the opinions of doctors and guidelines. Studies reporting the relative risk of acute cardiovascular events after aspirin withdrawal when compared with its continuation were not found. However, retrospective investigations revealed that aspirin withdrawal precedes up to 10.2% of acute cardiovascular syndromes. The time interval between discontinuation and acute cerebral events was 14.3 +/- 11.3 days, 8.5 +/- 3.6 days for acute coronary syndromes, and 25.8 +/- 18.1 days for acute peripheral arterial syndromes (P < 0.02 versus acute coronary syndromes). On aspirin-related bleeding risks, we obtained 41 (12 observational retrospective, 19 observational prospective, 10 randomized) studies, reporting on 49 590 patients (14 981 on aspirin). Baseline frequency of bleeding complications varied between 0 (skin lesion excision, cataract surgery) and 75% (transrectal prostate biopsy). Whilst aspirin increased the rate of bleeding complications by factor 1.5 (median, interquartile range: 1.0-2.5), it did not lead to a higher level of the severity of bleeding complications (exception: intracranial surgery, and possibly transurethral prostatectomy). Surveys amongst doctors on the management of this problem demonstrate wide variations. Available guidelines are scarce and in part contradictory. Only if low-dose aspirin may cause bleeding risks with increased mortality or sequels comparable with the observed cardiovascular risks after aspirin withdrawal, it should be discontinued prior to an intended operation or procedure. Controlled clinical studies are urgently needed.

Effect of Preoperative Aspirin Use on Postoperative Bleeding and Thromboelastography in Off-Pump Coronary Artery Bypass Operations

Background: Aspirin has been shown to effectively increase survival and reduce morbidity in patients with ischemic heart disease. Continued aspirin use during the preoperative period could increase the postoperative blood loss in patients who have on-pump coronary artery bypass grafting. This study aimed to determine the effect of continued aspirin use before off-pump CABG on intraoperative and postoperative bleeding and coagulation profile in thromboelastography. Methods: In 43 patients undergoing OPCAB, they were assigned aspirin user (n = 22), who received aspirin until the day of operation or nonaspirin user (n = 21), who discontinued aspirin before 7 days before the surgery. Intraoperative and postoperative bleeding and transfusion requirement were measured. TEG was performed and R, K, angle, maximum amplitude and TEG index was measured at preinduction and at 24 hours after surgery. Results: There were no differences in patient characteristics between aspirin users and nonaspirin users. We found no significant difference between postoperative bleeding and blood product requirements for the two groups. Similarly, we found no significant difference in the coagulation profiles. Conclusions: The use of aspirin continued preoperatively does not increase intraoperative and postoperative blood loss, and blood product requirement and influence on coagulation profile.

Long-term effects of intracoronary beta-radiation in balloon- and stent-injured porcine coronary arteries.

The data on the long-term safety and efficacy of intracoronary beta-radiation in animal models are limited. A total of 30 coronary arteries in 15 swine were subjected to balloon or stent injury followed by beta-radiation from a centered 32P source (2000 cGy to 1 mm beyond lumen surface) or a sham radiation procedure. The animals received aspirin for 6 months and ticlopidine for 30 days. Five of the 10 animals subjected to radiation died (at 5 days, 7 days, 3 months [n = 2], and 4 months) as a result of layered, occlusive thrombus at the intervention site (3 stent and 2 balloon injury sites). No deaths occurred in the control group. In the surviving animals, balloon-injured and irradiated vessels showed a trend toward larger lumens than controls (2.15 +/- 0.17 versus 1.80 +/- 0.08 mm2, P=0.06) and larger external elastic lamina areas (3.32 +/- 0.21 versus 2.62 +/- 0.10 mm2, P=0.003). In the stent-injured vessels from surviving animals, lumen, neointimal, and external elastic lamina areas were 3.58 +/- 0.33, 3.16 +/- 0.35, and 8.12 +/- 0.42 mm2 for irradiated vessel segments; these values were not different from those in controls (3.21 +/- 0.15, 2.84 +/- 0.27, and 7.76 +/- 0.28 mm2, respectively). Histologically, healing was complete in most survivors, although intramural fibrin and hemorrhage were occasionally seen. In the long-term (6 month) porcine model of restenosis, the inhibition by intracoronary beta-radiotherapy of the neointimal formation that is known to be present at 1 month is not sustained. This lack of effect on neointimal formation after balloon and stent arterial injury is accompanied by subacute and late thrombosis that leads to cardiac death on a background of continuous aspirin but relatively brief ticlopidine treatment.

One‐year outcome in multivessel coronary disease patients undergoing coronary stenting

The purpose of this study was to assess 1-year clinical outcome of patients with multivessel coronary artery disease (CAD) who underwent coronary stenting and were prospectively enrolled in the Registro Impianto Stent Endocoronarico (RISE). Of 939 consecutive patients included in the registry, 377 patients with angiographic evidence of multivessel CAD had a 1-year clinical follow-up. All patients underwent PTCA and single or multiple stenting in at least one vessel. Angiographic optimization was usually performed by using high-pressure balloon dilation. After the procedure, continuation of aspirin (at least 250 mg/day) was recommended, whereas the use of anticoagulation or ticlopidine was determined by the physician in charge of the patient in the various centers. Major adverse cardiac events were defined as death, Q-wave or non–Q-wave myocardial infarction and target vessel revascularization. Mean age of patients (311 men, 66 women) was 60 ± 10 years. Globally, there were 596 stents implanted (72% Palmaz-Schatz stents) in 434 vessels. In about 75% of the procedures, an inflation pressure > 12 atm was used. Angiographic success rate was 98.5%. After stenting, 77% of patients received antiplatelet treatment with ticlopidine and aspirin. During hospitalization, there were 34 major adverse cardiac events in 24 patients. At 1-year follow-up, 309 patients were alive and event-free; cumulative incidence of death, myocardial infarction, and repeat revascularization were 2.9%, 4.7%, and 10.8%, respectively. By Cox regression analysis, multiple stents implantation (HR 1.72, 95% CI 1–2.97), left anterior descending artery revascularization (HR 1.86, 95% CI 1.01–3.42), use of inflation pressure > 12 atm (HR 0.93, 95% CI 0.89–0.97), ticlopidine therapy (HR 0.41, 95% CI 0.23–0.74), and stent length (HR 1.03, 95% CI 1.01–1.05) were associated with 1-year major cardiac events. In patients with multivessel CAD undergoing stent implantation in at least one vessel, 1-year follow-up is favorable and the need for repeat revascularization procedures, based on clinical data, is lower than previously reported for conventional PTCA. Cathet. Cardiovasc. Intervent. 48:343–349, 1999. © 1999 Wiley-Liss, Inc.

One-year outcome in multivessel coronary disease patients undergoing coronary stenting.

The purpose of this study was to assess 1-year clinical outcome of patients with multivessel coronary artery disease (CAD) who underwent coronary stenting and were prospectively enrolled in the Registro Impianto Stent Endocoronarico (RISE). Of 939 consecutive patients included in the registry, 377 patients with angiographic evidence of multivessel CAD had a 1-year clinical follow-up. All patients underwent PTCA and single or multiple stenting in at least one vessel. Angiographic optimization was usually performed by using high-pressure balloon dilation. After the procedure, continuation of aspirin (at least 250 mg/day) was recommended, whereas the use of anticoagulation or ticlopidine was determined by the physician in charge of the patient in the various centers. Major adverse cardiac events were defined as death, Q-wave or non-Q-wave myocardial infarction and target vessel revascularization. Mean age of patients (311 men, 66 women) was 60 +/- 10 years. Globally, there were 596 stents implanted (72% Palmaz-Schatz stents) in 434 vessels. In about 75% of the procedures, an inflation pressure > 12 atm was used. Angiographic success rate was 98.5%. After stenting, 77% of patients received antiplatelet treatment with ticlopidine and aspirin. During hospitalization, there were 34 major adverse cardiac events in 24 patients. At 1-year follow-up, 309 patients were alive and event-free; cumulative incidence of death, myocardial infarction, and repeat revascularization were 2.9%, 4.7%, and 10.8%, respectively. By Cox regression analysis, multiple stents implantation (HR 1.72, 95% CI 1-2.97), left anterior descending artery revascularization (HR 1.86, 95% CI 1.01-3.42), use of inflation pressure > 12 atm (HR 0.93, 95% CI 0.89-0.97), ticlopidine therapy (HR 0.41, 95% CI 0.23-0.74), and stent length (HR 1.03, 95% CI 1.01-1.05) were associated with 1-year major cardiac events. In patients with multivessel CAD undergoing stent implantation in at least one vessel, 1-year follow-up is favorable and the need for repeat revascularization procedures, based on clinical data, is lower than previously reported for conventional PTCA. Cathet. Cardiovasc. Intervent. 48:343-349, 1999.

Delayed Traumatic Hemothorax on Ticlopidine and Aspirin for Coronary Stent

A 64-year-old man presented with worsening dyspnea on exertion and hemothorax of the left chest 7 days after discharge from the hospital on ticlopidine and aspirin after coronary stent placement to his left circumflex artery. He had suffered traumatic rib fractures to the seventh, eighth, and ninth left ribs 28 days before this presentation and 21 days before starting the ticlopidine. Results of chest radiography at discharge 7 days earlier while on aspirin and after brief IV heparin had been negative except for minimal atelectasis and rib fractures barely visible on posteroanterior view. The delayed hemothorax had lowered the peripheral blood hematocrit to 23% and required tube thoracostomy drainage and blood transfusion. The delayed traumatic hemothorax in this case occurred on treatment with ticlopidine and did not recur with continuation of aspirin alone.

Intractable upper gastrointestinal ulceration due to aspirin in patients who have undergone surgery for peptic ulcer

Background & Aims: Postsurgical ulcer recurrence is a challenging problem. The aim of this study was to define the role of aspirin in postsurgical ulcers. Methods: We studied 30 patients with postsurgical ulcer and aspirin abuse. Preoperatively 13 had stenosis, 7 bleeding, and 7 perforation or penetration; 18 had undergone vagotomy and 11 gastrectomy. Results: Of 30 patients, 15 admitted long-term aspirin use (1–4 g/day), whereas 15 denied use but had positive salicylate blood levels (15.1 ± 2.25 mg/100 mL; >1 mmol/L). Gastrin or gastric secretion was normal in the 24 patients tested. On follow-up, 3 (10%) healed after surgery (all stopped taking aspirin), whereas 27 continued and had new ulcers; 12 (44%) developed stenosis, and 6 (23%) developed bleeding. A second operation was required in 16 patients who had continued aspirin abuse, which was surreptitious in 10 (63%). Thirteen of these 16 had recurrent ulceration (7 [43%] with stenosis and 1 with bleeding); 1 died and 2 stopped taking aspirin and healed. A third operation was required in 8 patients. All had continued aspirin abuse (75% surreptitiously), and all again had relapses (3 with stenosis); 1 underwent an unsuccessful fourth operation, and 3 died. Conclusions: With continued aspirin abuse, recurrent ulceration is the rule, and complications, especially stenosis, are common. Surreptitious aspirin abuse, if discovered, is a clear contraindication to elective ulcer surgery, because aspirin-abuse ulceration is incurable by gastric surgery. GASTROENTEROLOGY 1998;114:883-892

The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke

Background Only a few small trials have compared antithrombotic therapy (antiplatelet or anticoagulant agents) versus control in acute ischaemic stroke, and none has been large enough to provide reliable evidence on safety or efficacy. Methods The International Stroke Trial (IST) was a large, randomised, open trial of up to 14 days of antithrombotic therapy started as soon as possible after stroke onset. The aim was to provide reliable evidence on the safety and efficacy of aspirin and of subcutaneous heparin. Half the patients were allocated unfractionated heparin (5000 or 12 500 IU bd [twice daily]) and half were allocated “avoid heparin”; and, in a factorial design, half were allocated aspirin 300 mg daily and half “avoid aspirin”. The primary outcomes were death within 14 days and death or dependency at 6 months. 19 435 patients with suspected acute ischaemic stroke entering 467 hospitals in 36 countries were randomised within 48 hours of symptom onset. Results Among heparin-allocated patients, there were non-significantly fewer deaths within 14 days (876 [9·0%] heparin vs 905 [9·3%] no heparin), corresponding to 3 (SD 4) fewer deaths per 1000 patients. At 6 months the percentage dead or dependent was identical in both groups (62·9%). Patients allocated to heparin had significantly fewer recurrent ischaemic strokes within 14 days (2·9% vs 3·8%) but this was offset by a similar-sized increase in haemorrhagic strokes (1·2% vs 0·4%), so the difference in death or non-fatal recurrent stroke (11·7% vs 12·0%) was not significant. Heparin was associated with a significant excess of 9 (SD 1) transfused or fatal extracranial bleeds per 1000. Compared with 5000 IU bd heparin, 12 500 IU bd heparin was associated with significantly more transfused or fatal extracranial bleeds, more haemorrhagic strokes, and more deaths or non-fatal strokes within 14 days (12·6% vs 10·8%). Among aspirin-allocated patients there were non-significantly fewer deaths within 14 days (872 [9·0%] vs 909 [9·4%]), corresponding to 4 (SD 4) fewer deaths per 1000 patients. At 6 months there was a non-significant trend towards a smaller percentage of the aspirin group being dead or dependent (62·2% vs 63·5%, 2p=0·07), a difference of 13 (SD 7) per 1000; after adjustment for baseline prognosis the benefit from aspirin was significant (14 [SD 6] per 1000, 2p=0·03). Aspirin-allocated patients had significantly fewer recurrent ischaemic strokes within 14 days (2·8% vs 3·9%) with no significant excess of haemorrhagic strokes (0·9% vs 0·8%), so the reduction in death or non-fatal recurrent stroke with aspirin (11·3% vs 12·4%) was significant. Aspirin was associated with a significant excess of 5 (SD 1) transfused or fatal extracranial bleeds per 1000; in the absence of heparin the excess was 2 (SD 1) and was not significant. There was no interaction between aspirin and heparin in the main outcomes. Interpretation Neither heparin regimen offered any clinical advantage at 6 months. The results suggest that if heparin is given in routine clinical practice, the dose should not exceed 5000 IU subcutaneously twice daily. For aspirin, the IST suggests a small but worthwhile improvement at 6 months. Taking the IST together with the comparably large Chinese Acute Stroke Trial, aspirin produces a small but real reduction of about 10 deaths or recurrent strokes per 1000 during the first few weeks. Both trials suggest that aspirin should be started as soon as possible after the onset of ischaemic stroke; previous trials have already shown that continuation of low-dose aspirin gives protection in the longer term.

Aspirin or heparin immediately after a stroke?

The International Stroke Trial (IST) published in this issue of The Lancet is the largest trial conducted of the acute treatment of ischaemic stroke. It included about 20 000 patients. It is a randomised open trial with four treatment groups equal in size: (1) aspirin 300 mg a day, (2) heparin at two doses (5000 or 12 500 IU twice a day), (3) aspirin plus heparin, and (4) no aspirin and no heparin. Treatment was started within 48 hours of the onset of a suspected acute ischaemic stroke and continued until discharge or for up to 14 days. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic strokeNeither heparin regimen offered any clinical advantage at 6 months. The results suggest that if heparin is given in routine clinical practice, the dose should not exceed 5000 IU subcutaneously twice daily. For aspirin, the IST suggests a small but worthwhile improvement at 6 months. Taking the IST together with the comparably large Chinese Acute Stroke Trial, aspirin produces a small but real reduction of about 10 deaths or recurrent strokes per 1000 during the first few weeks. Both trials suggest that aspirin should be started as soon as possible after the onset of ischaemic stroke; previous trials have already shown that continuation of low-dose aspirin gives protection in the longer term. Full-Text PDF

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS, EICOSANOIDS, AND COLORECTAL CANCER PREVENTION

A concise review of the literature that evaluates the risk of colorectal cancer among NSAID users has been presented. Animal studies document a protective effect of NSAIDs in preventing colorectal cancers in carcinogen-induced (AOM) models and in Min mice. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that these agents must be acting early in the adenoma-to-carcinoma sequence. Treatment of FAP patients with NSAIDs causes regression of adenomas that were already present before initiation of therapy. Many epidemiologic studies have examined the relationship between aspirin use and colorectal cancer. Most show a marked decrease in the relative risk (40% to 50%) of this tumor among continuous aspirin users. The appropriate dose and duration of aspirin treatment needed for optimal results are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is inhibition of cyclooxygenase. Presently, whether inhibition of COX-1 or COX-2 is required for the protective effect of aspirin and other NSAIDs is unclear. The authors and others have demonstrated that COX-2 is up-regulated from 2 to 50 fold in 85% to 90% of colorectal adenocarcinomas, making the COX-2 enzyme a more likely target. The authors have also reported a dramatic increase in COX-2 expression in colon tumors that develop in rats after AOM treatment. Drugs are currently being developed that preferentially inhibit either COX-1 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, these newly developed, selective NSAIDs may play a role in future chemoprevention strategies.

Growth markers in the human gastric mucosa during adaptation to continued aspirin administration.

The mechanism of gastric mucosal adaptation to continued aspirin (ASA) administration is unknown. We have investigated growth and proliferation markers in healthy subjects under prolonged ASA treatment. In eight healthy volunteers, ASA treatment (2 g/day) was continued for 14 days. Endoscopy was performed before medication; at days 3, 7, and 14 of ASA treatment; and at days 16 and 18 (2 and 4 days, respectively, after medication was ceased). Gastric biopsies from oxyntic and antral mucosa were studied by histology and by histochemistry for proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and epidermal growth factor receptor (EGFr). ASA treatment did not change the expression of EGF and EGFr significantly. The PCNA index showed local inconsistent variations. However, increased TGF-alpha expression after ASA was noted, particularly in hyperplastic surface epithelium. Edema and teleangiectases were common in gastric mucosa after ASA. An increasing incidence of foveolar hyperplasia was also noted in the antral mucosa. Healthy subjects on prolonged ASA treatment gradually develop parameters of chronic reactive gastritis accompanied by increased TGF-alpha expression in gastric surface epithelial cells, especially in hyperplastic areas.

Cyclic relapses of thrombotic thrombocytopenic purpura

A 24-year-old male patient was first observed with full-blown acute thrombotic thrombocytopenic purpura in 1991. Complete remission was achieved with plasma and plasmapheresis therapy, but in spite of continuous corticosteroid and aspirin administration, thrombocytopenic (megakaryocytic) relapses were observed every 26-30 days. Splenectomy and danazol failed to prevent the recurrence of the disease. Surprisingly, cyclosporin A (5 mg/kg/day) administration resulted in a complete transitional remission, but after dose reduction a less regular pattern of repeated milder recurrences was observed. Cryopreserved plasma, obtained from the patient during remission also proved to be effective in treating the last two thrombocytopenic episodes.

Transdermal modification of platelet function. A dermal aspirin preparation selectively inhibits platelet cyclooxygenase and preserves prostacyclin biosynthesis.

Even low doses of oral aspirin inhibit prostacyclin (prostaglandin [PG] I2) formation and cause gastrointestinal toxicity. We examined the skin as a novel route for continuous low-dose aspirin administration and selective inhibition of platelet cyclooxygenase in humans. Aspirin 250 or 750 mg/d for 10 days induced a dose-dependent inhibition of serum thromboxane (TX) B2. At the highest dose, five of six subjects responded, with a mean reduction in serum TXB2 of 95 +/- 3% (P = .003). Urinary 2,3-dinor TXB2, an index of in vivo TXA2 formation, decreased by 68 +/- 7% and recovered slowly, consistent with inhibition of platelet cyclooxygenase in vivo. In contrast, PGI2 biosynthesis, determined as excretion of 2,3-dinor-6-keto PGF1 alpha, was 81 +/- 5% of baseline at 10 days. Intravenous bradykinin increased PGI2 biosynthesis 5.1 +/- 1.6-fold (n = 4) before aspirin treatment. Oral aspirin 75 mg/d for 14 days abolished bradykinin-induced PGI2 formation, whereas dermal aspirin 750 mg/d had no effect despite similar inhibition of TXA2 biosynthesis. In five subjects, plasma aspirin and salicylate were determined after a single application of 750 mg. Aspirin was absorbed slowly, with peak levels of 0.24 +/- 0.11 micrograms/mL at 3 hours. Salicylate levels peaked at 6 to 12 hours, with plasma levels of 0.79 +/- 0.14 micrograms/mL. Thus, it is possible to achieve selective inhibition of platelet cyclooxygenase by aspirin applied to the skin. This approach may be applicable to other antiplatelet agents and be useful in patients at risk for gastrointestinal bleeding or toxicity.

Recombinant tissue type plasminogen activator and heparin in acute angina at rest

Because acute myocardial infarction (AMI) and unstable angina have a common pathogenesis, early thrombolytic treatment, proven to be highly beneficial in patients with AMI, may also be suitable for treating patients with severe unstable angina. A randomized, single-blind, multicenter, prospective, pilot study was conducted to determine whether early treatment with recombinant tissue type plasminogen activator (rt-PA) followed by a 3-day continuous heparin infusion and aspirin could reduce the 1-month incidence of unfavorable outcome (cardiovascular death, AMI, or recurrent angina at rest) in patients with acute angina at rest associated with ischemic electrocardiographic changes. Of the 60 patients enrolled in the trial, 30 were randomly assigned to receive rt-PA plus heparin and aspirin (rt-PA group) and 30 received heparin and aspirin alone (heparin group). An unfavorable outcome occurred in 7 (23.3%) of the 30 patients treated with rt-PA and in 13 (43.3%) of the 30 patients treated with heparin (odds ratio, 0.39; 95% CI, 0.13–1.2). One (3.3%) patient in the rt-PA group and five (16.6%) in the heparin group (16.6%) died or suffered a non-fatal AMI (odds ratio, 0.17; 95% CI, 0.02–1.6). Four patients died, all in the heparin group. The results of this study suggest that early treatment with rt-PA can improve the clinical outcome of unstable angina in a specific subgroup of patients with acute angina at rest.

Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. A placebo-controlled, randomized study.

The efficacy of aspirin for prevention of thrombotic graft occlusion after coronary artery bypass grafting (CABG) depends both on the dosage and time window of administration. Early and late graft patency were therefore assessed in a prospective, double-blind, randomized, placebo-controlled trial of aspirin, 324 mg daily, given within 1 hour of CABG. Angiographic graft patency was determined at 1 week (231 patients) and 1 year (219 patients) after CABG. The early vein graft occlusion rate was 1.6% on aspirin and 6.2% on placebo (p = 0.004), and late graft occlusion rate was 5.8% on continued aspirin and 11.6% on placebo (p = 0.01). New graft occlusion between 1 week and 1 year was less common in patients on aspirin than on placebo (4.3% versus 7.4%, p = 0.013). The protective effect of aspirin against occlusion persisted in most subgroups of graft type, graft flow, diameter of recipient artery, location of grafted artery, and endarterectomy. Mean chest tube blood loss for the first 24 hours was 571 ml for the aspirin group and 563 ml for the placebo group. Red cell transfusion requirements were 902 ml in the aspirin group and 934 ml in the placebo group (p = NS). The reoperation rate was 4.8% in the aspirin group and 1% in the placebo group (p = 0.1). Immediate postoperative administration of aspirin (324 mg) improves early graft patency and, with continued usage, protects against further occlusion up to 1 year after CABG. Postoperative blood loss was similar in the two groups; however, aspirin was associated with a nonsignificant higher rate of reoperation.

Slow release delivery of rioprostil by an osmotic pump inhibits the formation of acute aspirin-induced gastric lesions in dogs and accelerates the healing of chronic lesions without incidence of side effects

Rioprostil, a primary alcohol prostaglandin E 1 analog, inhibits gastric acid secretion and prevents gastric lesions induced by a variety of irritants in experimental animals. Because rioprostil is relatively short-acting, it would be of significant benefit clinically if its duration of action could be extended to allow once daily dosing. This investigation demonstrates that when administered via an osmotically driven pump (Osmet, Alza Corp.), rioprostil prevents the acute effects of aspirin on the gastric mucosa of dogs, accelerates the healing of aspirininduced gastric lesions, and heals preexisting aspirin-induced gastric lesions during chronic administration of aspirin. The potency of rioprostil against acute gastric lesion formation was greatest when delivered from a 24-hr release pump (ED 50 = 0.77 μg/kg/24 hr) and was 37 times greater than when administered as a single oral bolus. In addition, this activity occurred at doses which had little or no gastric antisecretory activity in betazole-stimulated Heidenhain pouch dogs. When delivered from a 24-hr pump, rioprostil (100 μg/kg/24 hr) healed preexisting aspirininduced gastric lesions within 8 days after removal of aspirin, or after 15 days during continued daily aspirin administration. Additional studies determined that administration of rioprostil at doses of 720, 1440, or 2160 μg/kg/24 hr (935–2805 times the gastroprotective ED 50 in 24 hr pumps) was well tolerated, with only slight, transient increases in body temperature, softening of the stools, and mild sedation at the highest dose. Administration of rioprostil daily for 5 days at 960 μ/kg/24 hr from 24-hr release pumps was also well tolerated by all dogs with no evidence of any accumulation of effect of rioprostil. In summary, administration of rioprostil via an osmotic pump increases its potency and duration of action against the gastric lesion-inducing effect of aspirin, and maintains a wide ratio of safety.

Aspirin and gastroduodenal injury.

Aspirin almost invariably causes acute mucosal injury to the stomach or duodenum as evidenced by erosions seen endoscopically, extensive surface cell disruption on histology, reduced mucosal potential difference and increased gastric bleeding. This injury is usually minor and transient, and not associated with symptoms. However, in the elderly recent aspirin intake may be associated with bleeding peptic ulcer, and along with other NSAIDs, may be causal in a third of cases. Regular chronic aspirin intake may also be associated with gastric ulceration. Such ulceration, however, although seemingly capable of healing despite continued aspirin or other NSAID use, may take longer to do so. Although aspirin and other NSAIDs have a strong connection with gastroduodenal problems the risk in an individual needs to be balanced by the likelihood of such events. Given their widespread use, the serious side effects of these drugs occur in only a small proportion of users. This, however, does not mitigate against careful prescription.

Gastric adaptation: Studies in humans during continuous aspirin administration

To study the process of gastric mucosal adaptation to aspirin administration, 14 normal men underwent a study with continued administration of aspirin. Endoscopic assessment, biopsies, and gastric wash collections for acid, mucus, and deoxyribonucleic acid recovery were performed weekly; aspirin was continued until the endoscopy showed minimal damage. Six subjects took 650 mg of aspirin b.i.d., and 8 took 650 mg q.i.d.; adaptation and resolution took longer with the higher dose (median 4.5 wk vs. 1 wk, p < 0.01). Despite improvement in mucosal appearance, gastric microbleeding remained elevated throughout aspirin administration. In contrast, deoxyribonucleic acid recovery (a marker for cellular exfoliation and regeneration) increased significantly just before the time of resolution, when, on average, it more than doubled. As no other biochemical or histologic changes could be associated with the resolution of damages, we conclude that gastric adaptation to chronic injury may involve increased cellular regeneration.