Oral antiplatelet agents in ACS: from pharmacology to clinical differences.

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Numerous clinical trials have established the value of antiplatelet therapies for ACS. Aspirin (ASA), thienopyridines and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS. Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Recently, a third generation of thienopyridines has been introduced represented by prasugrel that has demonstrated promising results in ACS patients treated with percutaneous coronary intervention (PCI). A number of nonthienopyridine oral antiplatelet drugs are under development, and one of them, ticagrelor has already been tested in a major phase III clinical trial, PLATO, with the inclusion of a broad spectrum of patients with ACS. The present review aims to discuss the present knowledge about the safety and efficacy of oral antiplatelet treatment of patients with ACS.

Bleeding risk with AZD6140, a reversible P2Y12 receptor antagonist, vs. clopidogrel in patients undergoing coronary artery bypass grafting in the DISPERSE2 trial.

AZD6140, the first reversible oral P2Y(12) receptor antagonist, exhibits greater and more consistent inhibition of platelet aggregation than the irreversible thienopyridine clopidogrel. As a result of its reversible effect, AZD6140 may pose less risk for bleeding when antiplatelet treatment cannot be stopped at least 5 days before coronary artery bypass graft (CABG) surgery or other invasive procedures. The Dose conflrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in NSTEMI (DISPERSE2) trial showed overall comparable bleeding rates with antiplatelet treatment with AZD6140 90 mg twice daily or 180 mg twice daily vs. clopidogrel 75 mg once daily in 984 patients with non-ST-elevation acute coronary syndromes. A post hoc exploratory analysis of bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE2 suggests reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%), and life-threatening bleeding (22% and 38% vs. 54%) with AZD6140 90 mg (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26) respectively. Trends suggested that major bleeding rates were reduced with AZD6140 (combined groups) vs. clopidogrel when treatment was stopped < or = 5 days prior to surgery (39% vs. 63%, p = 0.15) but not when treatment was stopped > 5 days before surgery (50% vs. 60%). This observation is consistent with the reversible binding of AZD6140 to the P2Y(12) receptor. Further prospective studies are planned to assess the relationship between this potential clinical benefit of AZD6140 and the reversibility of its antiplatelet effects.

Dietary fish oil reduces microvascular thrombosis in a porcine experimental model.

Microvascular thrombosis plays a significant role in the pathophysiology of ischaemic reperfusion injury. A fish oil-supplemented diet containing n-3 polyunsaturated fatty acids (PUFA) reduces thromboxane A(2) (TxA(2)) synthesis and, thus, vasoconstriction and platelet aggregation. The aim of this study was to elucidate whether n-3 PUFA in a porcine model of ischaemia and reperfusion injury 1) inhibit accumulation of platelets and fibrinogen in ischaemia-reperfusion injured tissue, 2) prolong the bleeding time, and 3) inhibit TxA(2) synthesis. Nine pigs were fed a standard diet supplemented with 7 g n-3 PUFA/day for 3 weeks. Nine pigs on the standard diet served as controls. Unilateral myocutaneous flaps were exposed to ischaemia for a period of 6 hours. Contralateral flaps were nonischaemic. Tissue contents of radioactive-labelled platelets and fibrinogen were measured after 4 hours of reperfusion. Platelet count, serum TxB(2), and the cutaneous bleeding time were measured before and after 3 weeks of diet. In the fish oil group, the accumulation of platelets was significantly reduced in all the myocutaneous flaps, except in the ischaemic skin part, when compared to control animals. Fibrinogen was significantly reduced in nonischaemic flaps, but not in ischaemic flaps. After the feeding period, the level of TxB(2) was significantly lowered in the fish oil group (p<0.01). No difference in the bleeding time was observed. Thus, dietary supplementation with n-3 PUFA inhibits the formation of microvasculatory thrombosis in this model.

29-week doxazosin treatment in patients with symptomatic benign prostatic hyperplasia. A double-blind placebo-controlled study.

In a placebo-controlled study, the safety and efficacy of the selective alpha 1-adrenoceptor-blocking agent doxazosin 4 mg once daily in the symptomatic treatment of benign prostatic hyperplasia (BPH) were evaluated. One hundred patients were primarily included in a 9-weeks study, and after this 75 patients accepted to continue in the present 20 weeks extension. Of the patients in the doxazosin-group (DG) 61% reported overall improvement against 53% in the placebo-group (PG)--(p = 0.56). In the DG, 49% of obstructive symptoms were improved compared to 27% in the PG (p < 0.01), and a reduction of 60% of irritative symptoms was found in the DG against 36% in the PG (p < 0.01). Daytime frequency was reduced by median 1.5 in the DG and remained unchanged in the PG (p < 0.01). Nocturia was reduced by median 1 and 0.5 respectively (p = 0.06). Maximum urinary flow rate (MFR) was improved by median 1.5 ml/s in the DG, while it deteriorated by median 0.5 ml/s in the PG (p < 0.05), Considering postvoid residual urine volume, cystometry variables (first sensation and bladder capacity), changes in sexual function and adverse events there was no difference between the two groups. In conclusion, doxazosin 4 mg once daily in long-term treatment of patients with BPH reduces both obstructive and irritative symptoms, daytime voiding frequency and although only slightly, significantly augments MFR without interference with sexual function and without other serious adverse effects.

Doxazosin treatment in patients with prostatic obstruction. A double-blind placebo-controlled study.

The safety and efficacy of the selective alpha 1-blocking agent doxazosin 4 mg once daily in the symptomatic treatment of benign prostatic hyperplasia were evaluated in a randomized, double-blind and placebo-controlled 9-week study of 100 patients. By patients' overall assessment of voiding difficulties, 79% in the doxazosin group (DG) and 44% in the placebo group (PG) reported improvement (p = 0.001). In the DG, improvement was noted in 63% of obstructive symptoms compared to 32% in the PG (p = 0.015), whereas improvement was noted in 76% and 45%, respectively, of irritative symptoms (p = 0.12). Daytime frequency was reduced by 1.5 in the DG and increased by 0.3 in the PG (p = 0.001), and nocturia was reduced by 1.1 and 1.0, respectively (p = 0.12). Maximum urinary flow rate was improved by 1.5 ml/s in the DG, while it deteriorated by 0.3 ml/s in the PG (p = 0.11). Considering postvoid residual urine volume, cystometry variables (first sensation and bladder capacity) and adverse events there was no difference between the two groups. In conclusion, doxazosin 4 mg once daily is safe and effective in relieving symptoms in patients with BPH.

Plasma thromboxane B2 as an early marker of acute graft rejection after heart transplantation: preliminary report.

Six patients undergoing heart transplantation were followed up by serial endomyocardial biopsies to detect signs of graft rejection and the plasma level of thromboxane B2 was measured at the same time. During the operative procedure and concomitant with histologic signs of acute graft rejection, the plasma level of thromboxane B2 significantly increased. After immunosuppressive treatment with steroids and either antithymocyte globulin or monoclonal antibody, regression of the histologic signs of rejection and a significant fall in the level of thromboxane B2 were documented. We conclude that the plasma level of thromboxane B2 may be useful as an early marker of acute graft rejection after heart transplantation.

Principles of thromboprophylaxis in surgical patients.

Thromboprophylactic treatment during surgery reduces mortality and morbidity. The type of prophylaxis may be individualized according to type of operation and presence of major risk factors, such as prior thromboembolism, malignancy, long duration of immobilization, and medical conditions. All patients over the age of 40, or even younger, who have major risk factors, and whose operations will last for more than 1 hour, may benefit from thromboprophylaxis. Available prophylactic methods allow for treatment with an acceptably low level of side effects and economic cost, when compared with the cost of diagnostics and treatment of thromboembolism.

Concurrent chemotherapy and radiation therapy followed by transhiatal esophagectomy for local-regional cancer of the esophagus.

Forty-three patients with local-regional squamous-cell carcinoma of the esophagus or adenocarcinoma of the esophagus, cardia, or gastroesophageal junction were treated with concurrent cisplatin, vinblastine, fluorouracil (5-FU), and radiation therapy (RT) over 21 days. A transhiatal esophagectomy (THE) was planned on day 42. Seventy-nine percent had T2 primaries by clinical staging and 56% had enlarged regional nodes (N) on computed tomographic (CT) scan. Forty-one patients completed the preoperative treatment and went to surgery (95% operability rate), and 36 (84%) were completely resected. Ten of the 41 operative candidates had no evidence of tumor in the resected esophagus and nodal tissue (tumor0 node0; T0N0), 24% complete response (CR). Myelosuppression was the major toxicity with grade 3 or 4 leukopenia in 93% of patients and two preoperative treatment-related deaths. At a median follow-up of 26 months, the median survival time (MST) of all 43 patients registered on study has not been reached. The MST of the 36 completely resected patients and the 10 complete responders has not been reached; 70% and 100%, respectively, are alive at 24 months. The MST by histology is 21 months for the 22 squamous patients and has not been reached for the 21 adenocarcinoma patients registered on study. In a prognostic factor analysis, clinical N status, histology, and the percent of cisplatin and vinblastine tolerated were significant predictors for survival. These survival results suggest a significant improvement over the 14-month MST observed in our previous trial using preoperative chemotherapy only in a similar patient population, and a 12-month MST in a historic control group undergoing THE. A randomized trial is now in progress to convincingly determine if survival is prolonged by this therapy.

Stress response and platelet function in minor surgery during epidural bupivacaine and general anaesthesia: effect of epidural morphine addition.

In a randomized study, thirty patients submitted to transarthroscopic meniscectomy were allocated to general or epidural anaesthesia with or without epidural morphine. Threshold concentration of collagen for platelet aggregation did not differ between the groups, but showed a similar pattern of increase, which was significant in the general anaesthesia group. Collagen-induced thromboxane-B2 synthesis was significantly lower in the epidural anaesthesia groups compared with the general anaesthesia group, and the addition of morphine caused a significant fall in thromboxane-B2 synthesis. The mean serum cortisol concentration increased in the general anaesthesia group, and decreased in the epidural groups. The difference between the groups was significant. Epidural morphine administration significantly decreased serum cortisol. During operation a thigh tourniquet was used. The removal of the tourniquet did not influence any of the measured variables. It can be concluded that the adrenocortical system is activated during general and inhibited during epidural anaesthesia. The addition of morphine during epidural anaesthesia further decreases the activity of the adrenocortical system, and the combined regime has an inhibiting effect on platelet function.

Dual inhibitory action of ATP on adrenergic neuroeffector transmission in rabbit pulmonary artery.

The aim of this study was to determine whether the inhibitory action of ATP on sympathetic neuroeffector transmission in the isolated pulmonary artery is due to ATP itself or one of its dephosphorylated breakdown products, ADP, AMP or adenosine. Furthermore, the mechanism of the inhibitory action was investigated. ATP (10(-6)-3 X 10(-4) M), the degradation-resistant ATP-analogue, beta, gamma-methylene-5'-triphosphate (10(-5)-3 X 10(-4) M), ADP (10(-6)-3 X 10(-4) M), AMP (10(-5)-3 X 10(-4) M), adenosine (10(-5)-3 X 10(-4) M) and 2-chloroadenosine (10(-7)-3 X 10(-4) M) reduced the contractions evoked by field-stimulation. This was also the case for prostaglandin E2 (3 X 10(-9)-3 X 10(-7) M), while prostaglandin F2 alpha (1.4 X 10(-8) M) slightly augmented the neurogenic response. The time course of the inhibitory effect of purinergic compounds on the stimulation evoked contractions was studied. In the case of ATP and ADP the inhibition was biphasic: an initial marked block (1 min. after drug addition) which in the continued presence of either compound recovered partially 10 min. later and then remained almost constant for another 90 min. The other purinergic agents caused a monophasic reduction. In the presence of indomethacin (5 X 10(-5) M), ATP and ADP also reduced the neurogenic contractions in a monophasic manner. Indomethacin did not alter the beta, gamma-methylene-5'-triphosphate-induced inhibition. Dilazep (3 X 10(-6) M) plus deoxycoformycin (3.6 X 10(-6) M), augmented the inhibitory effect of ATP. In contrast, theophylline (5 X 10(-5) M) did not alter the effect of ATP. The inhibitory effect of ATP (10(-4) M) on stimulation-evoked contractions was inversely proportional to the extracellular Ca2+ concentration (0.3-5.2 mM) and to frequency of stimulation (3-15 Hz). These results suggest that ATP initially causes a presynaptic inhibition of noradrenaline release evoked by field-stimulation. This phase I block is probably mainly due to an ADP-mediated short-lasting release of prostaglandins of the E type. The continuous inhibition (phase II) is probably due to ATP and its metabolites, possibly mainly adenosine. The phase II inhibition may possibly involve a decreased entry of Ca2+ into adrenergic nerve terminals during depolarization.

Effect of postoperative extradural morphine on lower urinary tract function.

The effect of postoperative extradurally administered morphine on lower urinary tract function was studied in female patients undergoing uterine surgery. Urodynamic measurements were made on the day before and on the day after the operation, using a DISA 2-channel carbon dioxide (CO2) cystomictrograph. In ten patients without postoperative urinary retention no changes in cystometry were found during morphine administration, while two patients who developed acute urinary retention had a marked increase in bladder capacity and of detrusor pressure. In contrast, the urethral pressure profile was unchanged in both groups of patients. Intravenously administered naloxone tended to normalize the bladder capacity in the patients with urinary retention. These findings seem to indicate a marked effect in some patients of extradurally administered morphine and the acute urinary retention, following morphine administration, may be treated with naloxone.

Prevention of postoperative deep venous thrombosis. Low-dose heparin versus graded pressure stockings.

In a prospective, controlled clinical study prevention of postoperative deep venous thrombosis by low-dose heparin (Heparin Leo 5 000 I.U. subcutaneously twice daily) was compared with graded compression stockings (TED stockings, Kendall Co.). One hundred and twelve patients, admitted during a period of one year for elective major surgery, were allocated to one of the two treatment groups. In order to detect deep venous thrombosis the 99mTc-plasmin test was performed before the operative procedure and again 5 days later. Ninety-seven patients completed the study (45 patients in the heparin group and 52 patients in the stocking group). Venous thromboembolism was detected in 4 patients (8.9%) in the heparin group and in 3 patients (5.8%) in the stocking group (p greater than 0.05). In 6 patients the plasmin test was positive and one patient in the heparin group died following pulmonary embolism. It is concluded that graded compression stockings can be used as an alternative to low-dose heparin for prophylaxis against deep venous thrombosis in elective general surgery.

A new automated technique for platelet aggregation measurement.

A Multistat III Centrifugal Analyser (MCA) was used to measure platelet aggregation in vitro. It has a capacity of about 40 samples per h. In the analyser platelet-rich plasma and collagen-reagent were mixed, and the turbidity was measured as a function of time. The results were presented in arbitrary units ( arb . units), i.e. change in turbidity per min X 1000. The estimated 0.95 reference range was 50-95 arb . units, (n = 46) and the coefficient of correlation between MCA results and results obtained by conventional aggregometry ( Fibromat ) was 0.85 (P less than 0.001). The MCA method registered 50-75% reduction of platelet aggregation after intake of low dose acetylsalicylic acid (ASA) (1.2-4.0 mg/kg) during 3 days in 19 subjects. The MCA method is suitable to monitor ASA treatment routinely in order to establish an individual appropriate ASA dose during prophylactic treatment of arterial thromboembolic disease.

Deep vein thrombosis detection by 99mTc-plasmin test and phlebography.

During a 2-year period the diagnostic value of 99mTc-labelled-plasmin test was evaluated in 63 patients admitted with clinical signs of deep vein thrombosis (DVT). In comparison with a conventional phlebography the diagnostic sensitivity and specificity of the plasmin test was 0.97 and 0.55, respectively. The predictive value in positive cases was 0.79 and in negative 0.92. The sensitivity was highest for thrombosis in the calf and popliteal regions, while the specificity was higher for thrombosis in the femoral veins. It is concluded that the 99mTc-labelled-plasmin test is suitable for DVT-screening in groups of high-risk patients and is simple and rapid. In positive cases the DVT diagnosis must be verified by phlebography.

Heparin-induced increase in serum levels of aminotranferases. A controlled clinical trial.

Sixty-four patients over the age of 40 years, undergoing elective surgery of at least one hour's duration, were randomized to treatment with either a thromboembolic deterrent ( TED ) stocking (Kendall Co.) or subcutaneous low-dose heparin 5 000 IU every 12 hours. Serum levels of alanine aminotransferase (S-ALAT), aspartate aminotransferase (S-ASAT), gamma-glutamyl transpeptidase (S-gamma-GT) and alkaline phosphatase (S-ALP) were measured. S-ALAT increased significantly on the 5th and 10th postoperative day, from 27 +/- 2 (x +/- SE) to 40 +/- 4 (p less than 0.01) and 55 +/- 7 U/l (p less than 0.001), respectively, in the heparin group and was significantly higher in the heparin than in the TED group both on the 5th (p less than 0.01) and 10th (p less than 0.05) postoperative day. S-ASAT and S-gamma-GT increased significantly during heparin treatment, but did not differ significantly from the values of the TED group. No change in S-ALP was registered in either group. It is concluded that prophylactic treatment with low-dose heparin induces a significant increase in S-aminotransferase levels, especially in S-ALAT. The phenomenon has profound differential diagnostic implications in conditions such as pulmonary embolism and acute myocardial infarction.