Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial

OBJECTIVE: We investigated in general practice the efficacy of antiplatelets and antioxidants in primary prevention of cardiovascular events in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: The Primary Prevention Project (PPP) is a randomized, open trial with a two-by-two factorial design aimed to investigate low-dose aspirin (100 mg/day) and vitamin E (300 mg/day) in the prevention of cardiovascular events in patients with one or more cardiovascular risk factors. The primary end point was a composite end point of cardiovascular death, stroke, or myocardial infarction. A total of 1,031 people with diabetes in the PPP, aged >/=50 years, without a previous cardiovascular event were enrolled by 316 general practitioners and 14 diabetes outpatient clinics. RESULTS: The PPP trial was prematurely stopped (after a median of 3.7 years) by the independent data safety and monitoring board because of a consistent benefit of aspirin compared with the control group in a population of 4,495 patients with one or more major cardiovascular risk factors. In diabetic patients, aspirin treatment was associated with a nonsignificant reduction in the main end point (relative risk [RR] = 0.90, 95% CI 0.50-1.62) and in total cardiovascular events (0.89, 0.62-1.26) and with a nonsignificant increase in cardiovascular deaths (1.23, 0.69-2.19). In nondiabetic subjects, RRs for the main end point, total cardiovascular events, and cardiovascular deaths were 0.59 (0.37-0.94), 0.69 (0.53-0.90), and 0.32 (0.14-0.72), respectively. No significant reduction in any of the end points considered could be found with vitamin E in either diabetic or nondiabetic subjects. CONCLUSIONS: Our data suggest a lower effect of primary prevention of cardiovascular disease (CVD) with low-dose aspirin in diabetic patients as opposed to subjects with other cardiovascular risk factors. If confirmed, these findings might indicate that the antiplatelet effects of aspirin in diabetic patients are overwhelmed by aspirin-insensitive mechanisms of platelet activation and thrombus formation, thus making the balance between benefits and harms of aspirin treatment unfavorable. Further large-scale trials investigating the role of aspirin in the primary prevention of CVD in diabetic patients are urgently needed.     

Access to rehabilitation facilities in an unselected hospital population affected by acute stroke

The aim of this study was to evaluate the selection criteria and characteristics of the patients who have access to rehabilitation facilities after having experienced an acute stroke.Between January 1993 and February 1994, 383 patients were recruited in 13 hospitals in Lombardy, and telephonically followed up four months after study entry. The data were collected by members of the Associazione Volontari Ospedalieri (Hospital Volunteers' Association).The 4-month mortality rate was 23%. The primary selection criterion for gaining access to rehabilitation facilities was the degree of disability; the secondary factor was age. Rehabilitation facilities were not available to very severely afflicted or self-sufficient patients, but were preferentially made available to young, partially-dependent patients. A rehabilitative intervention within the first month was made available to fewer than 50% of the patients for whom it was indicated.The absence of care for elderly patients and the delay in its availability for those who actually receive it underline the need for new organisational methods. The data presented here also show that voluntary associations can work as observers of the health service. A more complete study is required in order to understand the real dimensions of the problem and the clinical and social characteristics of the population involved.This work was supported by the Associazione Volontari Ospedalieri.     

Ditazole and platelets. I. Effect of ditazole on human platelet function in vitro.

Ditazole (4,5-diphenyl-2-bis-(2-hydroxyethyl)-aminoxazol) has been shown to be a strong in vitro inhibitor of human platelet aggregation brought about by release reaction inducers; in contrast, it did not significantly affect primary ADP-induced aggregation. Ditazole strongly inhibited the release of platelet-bound 14C-serotonin under the influence of Thrombofax, whereas it did not interfere with the transport and storage of serotonin in nonstimulated platelets. The effect of ditazole was not potentiated by acetylsalicylic acid. Ditazole also inhibited ADP-reptilase clot retraction and modified thrombin-induced clot formation. The inhibition of platelet aggregation exerted by ditazole in plasma could be removed following gel filtration of platelets on Sepharose 2-B gel. This would indicate that ditazole does not act on platelets by a 'hit and run' mechanism.     

Evidence of a warfarin-sensitive cancer procoagulant in V2 carcinoma

Rabbit V2 carcinoma tissue is the tumor in which cancer procoagulant activity (CP) was first described, purified and identified as a cysteine proteinase able to activate F X directly. In the present study we show that CP of V2 carcinoma extracts is depressed in its biological activity (although the antigen is present) by warfarin treatment. The biochemical basis for this effect is offered by the identification of Vit.K-dependent gamma-carboxylase in the microsomal fraction of the tumor tissue. V2 carcinoma tissue had very low endogenous substrate(s) of tumor carboxylase in basal conditions but this increased threefold after warfarin. The accumulation of endogenous substrate(s) and the depression of the CP activity by warfarin raises the possibility that CP represents at least one of the substrates for gamma-glutamyl carboxylase in this experimental tumor tissue.     

Von Willebrand factor, plasminogen activator inhibitor-1 and C-reactive protein are markers of thrombolytic efficacy in acute myocardial infarction.

Plasma von Willebrand factor, plasminogen activator inhibitor activity and C-reactive protein were assessed as markers of coronary recanalisation in 30 patients with acute myocardial infarction receiving tissue-type plasminogen activator (t-PA). Blood samples were taken before t-PA (time 0), 4-hourly for 24 h and daily up to 72 h. A continuous electrocardiogram was recorded in the first 24 h. Coronary arteriography was performed 90 min and 24 h after the start of t-PA. Patients with a patent infarct artery (n = 17), compared to those with occluded artery (n = 13), showed a fall in von Willebrand factor from 0 to 24 h (p = 0.001), a greater fall in plasminogen activator inhibitor from 24 to 48 h (p = 0.04) and a fall in C-reactive protein from 48 to 72 h (p = 0.002). The accuracy of these indices compared favourably with time to peak plasma MB creatine kinase and > or = 50% resolution of maximal ST-deviation on the electrocardiogram. Thus, changes in plasma von Willebrand factor, plasminogen activator inhibitor and C-reactive protein during the first 3 days of myocardial infarction are indicative of thrombolytic efficacy. Their concordant behaviour may reflect a common regulatory mechanism.     

Heparin counteracts the antiaggregating effect of prostacyclin by potentiating platelet aggregation

It has recently been reported that heparin neutralizes the inhibitory effect of prostacyclin (PGI2) on human platelet aggregation. The mechanism of this interaction has not yet been unequivocally established. We present here evidence that heparin (Liquemin Roche) does not react directly with PGI2 but counteracts its inhibitory effect by potentiating platelet aggregation. In the absence of heparin, PGI2 was a less effective inhibitor of platelet aggregation induced by the combination of ADP and serotonin than by ADP alone. Moreover, the inhibitory effect of PGI2 was similarly reduced when increasing the concentrations of ADP (in the absence of heparin). The lack of a specific interaction between heparin and PGI2 is supported by the observation that, in the presence of heparin, other prostaglandins such as PGD2 and PGE1 and a non-prostanoid compound such as adenosine also appeared to lose their inhibitory potency. It is concluded that heparin opposes platelet aggregation inhibitory effect of PGI2 by enhancement of platelet aggregation.     

Plasmatic and vascular factors of the hemostatic system in rats receiving an estrogen-progestogen combination

Treatment of rats for 10 estral cycles with an estrogen-progestogen combination giving 100% infertility triggered a vascular response characterized by increased prostacyclin activity in arterial walls and increased systolic blood pressure. In contrast, plasma fibrinolytic activity and physiological coagulation inhibitors as well as vascular fibrinolytic activity were not changed by this treatment. The same rats tended to have shorter occlusion times of an aortic prosthesis, and could represent a useful model to study the blood-vessel-wall interplay during oral contraceptive treatment.