title: Assessment of blood pressure during treatment with naproxen or ibuprofen in hypertensive patients treated with hydrochlorothiazide. Anticoagulant therapy after acute myocardial infarction. Relation of therapeutic benefit to patient's age, sex, and severity of infarction. Randomized Trial of Thrombolysis Versus Heparin in Unstable Angina Do trandolapril and indomethacin influence renal function and renal functional reserve in hypertensive patients? Enhanced blood pressure response to cyclooxygenase inhibition in salt-sensitive human essential hypertension. Effects of captopril and ticlopidine, alone or in combination, in hypertensive patients with intermittent claudication. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study Prediction of 1-year survival after thrombolysis for acute myocardial infarction in the global utilization of streptokinase and TPA for occluded coronary arteries trial. Does chronic aspirin treatment increase blood pressure in man? Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril. Superiority of Clopidogrel Versus Aspirin in Patients With Prior Cardiac Surgery Aspirin, Warfarin, or the Combination for Secondary Prevention of Coronary Events in Patients With Acute Coronary Syndromes and Prior Coronary Artery Bypass Surgery Influence of aspirin usage on blood pressure: dose and administration-time dependencies. Comparative effects of nabumetone, sulindac, and ibuprofen on renal function. The effects of nonsteroidal anti-inflammatory drugs on blood pressures of patients with hypertension controlled by verapamil. Effects of non-steroidal anti-inflammatory drugs on prostacyclin and thromboxane biosynthesis in patients with mild essential hypertension. Alcohol consumption and risk of coronary heart disease by diabetes status. Effect of aspirin on mortality in women with symptomatic or silent myocardial ischemia. Israeli BIP Study Group. Comparative Safety and Tolerability of Clopidogrel and Aspirin Antihypertensive effect of the combination of fosinopril and HCTZ is resistant to interference by nonsteroidal antiinflammatory drugs. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. No adverse effect of non-steroidal anti-inflammatory drugs, sulindac and diclofenac sodium, on blood pressure control with a calcium antagonist, nifedipine, in elderly hypertensive patients. Haemodynamic changes induced by the correction of anaemia by erythropoietin: role of antiplatelet therapy. Comparison of two aspirin doses on ischemic stroke in post-myocardial infarction patients in the warfarin (Coumadin) Aspirin Reinfarction Study (CARS). Potential mechanisms by which nonsteroidal anti-inflammatory drugs elevate blood pressure: the role of endothelin-1. Interaction between nonsteroidal anti-inflammatory drug intake and calcium-channel blocker-based antihypertensive treatment in the Syst-Eur trial Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization. EXCITE Trial Investigators. Evaluation of Oral Xemilofiban in Controlling Thrombotic Events. [Reduction of the antihypertensive effects of enalapril by indomethacin. Its independence from renal sodium retention]. Renovascular effects of nonprescription ibuprofen in elderly hypertensive patients with mild renal impairment. Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with methotrexate, cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine alone. Efficacy of antiplatelet treatment in hypertensive patients with TIA or stroke. Secondary stroke prevention with low-dose aspirin, sustained release dipyridamole alone and in combination. ESPS Investigators. European Stroke Prevention Study. Influence of non-steroidal anti-inflammatory drugs on renal function and 24 h ambulatory blood pressure-reducing effects of enalapril and nifedipine gastrointestinal therapeutic system in hypertensive patients Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico II (GISSI-2), and The International Study Group. Treatment of hypertension with dihydropyridine calcium antagonists and aspirin. The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons. Effect of aspirin on blood pressure in hypertensive patients taking enalapril or losartan. Diabetes mellitus, glycoprotein IIb/IIIa blockade, and heparin: evidence for a complex interaction in a multicenter trial. EPILOG Investigators. DRUG-INDUCED INHIBITION OF PLATELET FUNCTION DELAYS PROGRESSION OF PERIPHERAL OCCLUSIVE ARTERIAL DISEASE: A Prospective Double-Blind Arteriographically Controlled Trial Randomised trial of prophylactic daily aspirin in British male doctors Blood pressure, stroke, and coronary heart disease: Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias Gastroduodenal tolerance of 75 mg clopidogrel versus 325 mg aspirin in healthy volunteers. A gastroscopic study. Antiplatelet therapy is effective in primary prevention of myocardial infarction in patients with a previous cerebrovascular ischemic event. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial Assessment of blood pressure during naproxen therapy in hypertensive patients treated with nicardipine. Indomethacin and cyclosporin together produce marked renal vasoconstriction in humans Study on the possible interaction between tenoxicam and atenolol in hypertensive patients. Non-steroidal anti-inflammatory drugs and blood pressure. Effect of indomethacin on blood pressure control during treatment with nitrendipine. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. Stroke in patients with acute coronary syndromes: incidence and outcomes in the platelet glycoprotein IIb/IIIa in unstable angina. Receptor suppression using integrilin therapy (PURSUIT) trial. The PURSUIT Investigators. Clopidogrel compatibility with concomitant cardiac co-medications: a study of its interactions with a beta-blocker and a calcium uptake antagonist. Controlled trial of aspirin in cerebral ischemia Amlodipine and haemodynamic effects of cyclo-oxygenase inhibition. Different patterns of renal prostaglandins I2 and E2 in patients with essential hypertension with low to normal or high renin activity Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators. Effect of low-dose aspirin on thromboxane production and the antihypertensive effect of captopril. Effect of ketoprofen on blood pressure, endocrine and renal responses to chronic dosing with captopril in patients with essential hypertension. The influence of ticlopidine on the natural course of retinal vein occlusion. Changes in peripheral hemodynamics and vasodilating prostaglandins after high-dose short-term ibuprofen in chronically treated hypertensive patients. Hemodynamic and humoral effects of low-dose aspirin in treated and untreated essential hypertensive patients. Cyclooxygenase-2–Specific Inhibitors and Cardiorenal Function: A Randomized, Controlled Trial of Celecoxib and Rofecoxib in Older Hypertensive Osteoarthritis Patients Effects of aspirin on angiotensin-converting enzyme inhibition and left ventricular dilation one year after acute myocardial infarction. Ticlopidine lowers plasma fibrinogen in patients with polycythaemia rubra vera and additional thrombotic risk factors. A double-blind controlled study. Preventive treatment of cerebral transient ischemia: comparative randomized trial of pentoxifylline versus conventional antiaggregants.
abstract: This study determined the effect of nonsteroidal anti-inflammatory drug ( NSAID ) administration on blood pressure in hypertensive patients taking hydrochlorothiazide ( HCTZ ) . Ninety-seven patients with mild essential hypertension and a musculoskeletal indication for NSAID use were studied in a three-phase , multi-center , double-blind , r and omized , parallel study based in 15 academic and community clinics . Patients served as their own controls . Patients with stable hypertension , not taking antihypertensive or NSAID medications , were treated with HCTZ 50 mg/day . After 4 to 5 weeks of treatment and documented stable blood pressure , naproxen 375 mg twice a day or ibuprofen 800 mg three times a day was added . Blood pressure was measured at 2 and 4 weeks of NSAID therapy . The average diastolic blood pressure was 97.5 + /- 2.4 mm Hg and the average of the mean arterial pressure ( MAP ) was 116.8 + /- 6.04 before treatment with HCTZ . Hydrochlorothiazide treatment decreased diastolic blood pressure to 83.1 + /- 5.6 mm Hg , and MAP to 101.1 + /- 6.5 mm Hg . With naproxen or ibuprofen treatments , mean diastolic blood pressure increased less than 3 mm Hg . At 2 weeks , ibuprofen increased diastolic blood pressure by 2.6 mm Hg ( P = .004 ) and naproxen increased diastolic blood pressure 0.7 mm Hg ( P = .40 ) . Both ibuprofen and naproxen significantly increased diastolic pressure at 4 weeks ( 2.1 mm Hg , P = .042 ; and 1.8 mm Hg , P = .043 , respectively ) . There was no correlation between the pre-NSAID blood pressure and the magnitude of change after 2 or 4 weeks of treatment . Changes in MAP reflected a pattern similar to diastolic pressure . ( ABSTRACT TRUNCATED AT 250 WORDS The value of anticoagulant therapy after acute myocardial infa rct ion has been assessed in 1,136 patients admitted to the Bronx Municipal Hospital Center . The treatment reduced the overall mortality in women from 31 % to 15 % , particularly those 55 years of age or over , with moderately severe infa rct ion . The low overall mortality in control men ( 16 % ) was not reduced with treatment , though there was significant reduction of the mortality in a subgroup of men with moderately severe infa rct ion showing Q-wave evolution . Age and sex , as well as the severity of the episode of acute myocardial infa rct ion , are important in determining whether anticoagulant therapy is likely to be beneficial Background The clinical usefulness of intravenous thrombolytic therapy in unstable angina is currently unknown , despite the pathogenetic similarity of this entity to acute myocardial infa rct ion , for which thrombolysis has enjoyed great success . To compare the clinical benefit of intravenous urokinase with that of conventional antithrombotic therapy in preventing the progression of unstable angina to new myocardial infa rct ion , intractable angina , or death within the first 96 hours after hospitalization , 149 patients with unstable angina were r and omized to one of two intravenous thrombolytic strategies . Methods and Results Forty-nine patients received 3 million units urokinase i.v . over 90 minutes plus intravenous heparin ( group A ) ; 47 patients received unblinded 3 million units urokinase i.v . plus 325 mg aspirin p.o . daily ( group B ) ; and 53 patients received placebo thrombolytic infusion plus full-dose heparin ( group C ) . The primary end point of this trial was 96-hour clinical status . There were no significant differences in the baseline characteristics ( age , sex , previous myocardial infa rct ion , hypertension prevalence , diabetes , tobacco use , or previous revascularization ) among the three groups . Despite an excess of minor untoward reactions for the urokinase groups ( chills , 26.5 % and 23.4 % for groups A and B versus 0 % for group C ; p<0.01 ) , there was no significant difference with respect to major bleeds ( two , none , and two for groups A , B , and C , respectively;p = NS ) . At 96 hours after presentation , no significant difference emerged in the incidence of new cardiac events : new myocardial infa rct ions developed in 10.2 % of group A , 6.4 % of group B , and 3.8 % of group C ( p = NS ) ; intractable angina occurred in 6.1 % of group A , 10.6 % of group B , and 9.4 % of group C ( p = NS ) . There were no deaths . All three groups encountered a similar incidence of overall cardiac events : 16.31 % , 17.0 % , and 13.2 % for groups A , B , and C , respectively ( p = NS ) . Although trial enrollment was to extend to 600 patients , interim analysis led to early cessation of enrollment due to a negative trend in respect to outcome after thrombolysis . Conclusions High-dose intravenous urokinase followed by either heparin or aspirin can be safely administered to a broad , unselected group of patients with unstable angina . However , this study suggests that no clinical advantage is conferred by urokinase , with either adjunctive antithrombotic therapy over st and ard heparin therapy alone , when given relatively late ( mean , 8.7 hours ) after admission for unstable angina . A possible detrimental effect can not be excluded AIMS To assess the effect of tr and olapril ( 2 mg once daily ) and indomethacin ( 25 mg three times daily ) , alone and in combination , on renal function and renal functional reserve in hypertensive patients ( DBP 95 - 115 mmHg ) requiring regular non-steroidal anti-inflammatory drugs ( NSAIDs ) . METHODS R and omized , double-blind , placebo-controlled , four way crossover design . After 3 weeks treatment renal plasma flow ( RPF ) and glomerular filtration rate ( GFR ) were measured using the p-aminohippurate ( PAH ) and inulin methods . Renal functional reserve was estimated by measuring RPF and GFR at the end of an intravenous infusion of dopamine 2 microg kg(-1 ) and 10 % amino acid solution . RESULTS There was no significant difference in RPF between treatments : -22.79 ml min(-1 ) ( 95 % CI -54.82 , 9.24 ) for placebo and tr and olapril , -10.37 ml min(-1 ) ( 95 % CI -30.7 , 9.96 ) for placebo and indomethacin , -14.78 ml min(-1 ) ( 95 % CI -50.33 , 20.77 ) for placebo and tr and olapril with indomethacin . There was no significant difference in functional reserve RPF between treatments : -34.96 ml min(-1 ) ( 95 % CI -119.8 , 49.88 ) for placebo and tr and olapril , 29.78 ml min(-1 ) , -15.18 , 74.74 ) for placebo and indomethacin , and -25.84 ml min(-1 ) ( 95 % CI -87.62 , 35.94 ) for placebo and tr and olapril with indomethacin . There was no significant difference in GFR between treatments : -1.01 ml min(-1 ) ( 95 % CI -7.45 , 5.42 ) for placebo and tr and olapril , -7.88 ml min(-1 ) ( 95 % CI -15.08 , -0.68 ) for placebo and indomethacin , and -0.36 ml min(-1 ) ( 95 % CI -7.58 , 6.86 ) for placebo and tr and olapril with indomethacin . There was no significant difference in functional reserve GFR between treatments : 5.13 ml min(-1 ) ( 95 % CI -4.97 , 15.23 ) for placebo and tr and olapril , 6.31 ml min(-1 ) ( 95 % CI -1.88 , 14.5 ) for placebo and indomethacin , 7.21 ml min(-1 ) ( 95 % CI 1.26 , 13.16 ) for placebo and tr and olapril with indomethacin . CONCLUSION In hypertensives chronic treatment with NSAIDs or ACEI alone or in combination did not change RPF or GFR and did not change renal functional reserve capacity of RPF or GFR To evaluate the influence of salt sensitivity on the blood pressure response to oral indomethacin treatment , we studied 35 hospitalized essential hypertensive patients ( 24 men and 11 women , aged from 40 to 55 years ) . During a normal NaCl intake ( 120 mmol Na+ per day ) , patients were assigned to receive in a r and omized double-blind fashion either 200 mg indomethacin ( 25 patients ) or placebo ( 10 patients ) for 5 days . Two weeks after the interruption of indomethacin treatment , during which the normal NaCl intake was continued , salt sensitivity was assessed by giving each patient a high ( 220 mmol Na+ per day for 10 days ) and then a low ( 20 mmol Na+ per day for 10 days ) NaCl diet . Blood pressure changes were evaluated , and the measurement taken at the end of the 2 weeks under normal sodium intake was considered baseline blood pressure . Patients were classified as salt sensitive when a diastolic blood pressure change of 10 mm Hg or more occurred after both low and high periods of sodium intake . In salt-resistant patients treated with indomethacin ( n = 12 , nine men and three women , mean age 50.5 + /- 3.7 years ) , neither blood pressure ( systolic blood pressure from 150.8 + /- 11.2 to 154.6 + /- 9.3 mm Hg , NS ; diastolic blood pressure from 99.3 + /- 2.1 to 101.1 + /- 4.4 mm Hg , NS ) nor the urinary Na+ excretion ( from 108.1 + /- 20.9 to 97.9 + /- 9.1 mmol/24 hr , NS ) was significantly affected by the drug . ( ABSTRACT TRUNCATED AT 250 WORDS Twenty four male hypertensive patients suffering also from peripheral obstructive arterial disease were r and omly subdivided in two groups and after a period of farmacological wash-out of one month Group I was treated with Captopril ( C 50 mg bid ) or Ticlopidine ( T 250 mg bid ) for three months and then with the association C plus T for three months again . After placebo administration for one month , patients were further treated with C plus T at low doses ( 25 mg bid and respectively 250 mg daily ) . In the first part of the study , patients of Group II received an inverse sequence of the drugs ( before Ticlopidine 250 mg bid and then Captopril 50 bid ) . In both groups of patients C induced a significant decrease of blood pressure and an increase of PFWD , TWD , and WI . T did not modify blood pressure but slightly increased PFWD , TWD , and WI . The improvement was more evident during administration of C plus T , whereas placebo administration induced a trend toward baseline values . Finally , the chronic administration of C plus T for twelve months induced a further improvement of all considered parameters . In conclusion , chronic administration of C plus T may be useful in the treatment of hypertensive patients suffering from intermittent claudication  , improving significantly PFWD and TWD BACKGROUND Despite the use of aspirin , there is still a risk of ischaemic events after percutaneous coronary intervention ( PCI ) . We aim ed to find out whether , in addition to aspirin , pretreatment with clopidogrel followed by long-term therapy after PCI is superior to a strategy of no pretreatment and short-term therapy for only 4 weeks after PCI . METHODS 2658 patients with non-ST-elevation acute coronary syndrome undergoing PCI in the CURE study had been r and omly assigned double-blind treatment with clopidogrel ( n=1313 ) or placebo ( n=1345 ) . Patients were pretreated with aspirin and study drug for a median of 6 days before PCI during the initial hospital admission , and for a median of 10 days overall . After PCI , most patients ( > 80 % ) in both groups received open-label thienopyridine for about 4 weeks , after which study drug was restarted for a mean of 8 months . The primary endpoint was a composite of cardiovascular death , myocardial infa rct ion , or urgent target-vessel revascularisation within 30 days of PCI . The main analysis was by intention to treat . FINDINGS There were no drop-outs . 59 ( 4.5 % ) patients in the clopidogrel group had the primary endpoint , compared with 86 ( 6.4 % ) in the placebo group ( relative risk 0.70 [ 95 % CI 0.50 - 0.97 ] , p=0.03 ) . Long-term administration of clopidogrel after PCI was associated with a lower rate of cardiovascular death , myocardial infa rct ion , or any revascularisation ( p=0.03 ) , and of cardiovascular death or myocardial infa rct ion ( p=0.047 ) . Overall ( including events before and after PCI ) there was a 31 % reduction cardiovascular death or myocardial infa rct ion ( p=0.002 ) . There was less use of glycoprotein IIb/IIIa inhibitor in the clopidogrel group ( p=0.001 ) . At follow-up , there was no significant difference in major bleeding between the groups ( p=0.64 ) . INTERPRETATION In patients with acute coronary syndrome receiving aspirin  , a strategy of clopidogrel pretreatment followed by long-term therapy is beneficial in reducing major cardiovascular events , compared with placebo BACKGROUND When a patient survives thrombolysis for acute myocardial infa rct ion , little information from large studies exists from which to estimate prognosis during follow-up visits . METHODS AND RESULTS Baseline , in-hospital , and later survival data were collected from 41 021 patients enrolled in Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries , a r and omized trial of 4 thrombolytic-heparin regimens with st and ard aspirin and beta-blockade .  Cox proportional hazards models were developed to predict 1-year survival in 30-day survivors ( n=37 869 ) from baseline clinical and ECG factors and in-hospital factors ; a combined model then was developed ( C-index 0.800 ) . The model was simplified into a nomogram to predict individual outcomes ( C-index 0.754 ) . Factors reflecting demographics ( advanced age , lighter weight ) , larger infa rct ions ( higher Killip class , lower blood pressure , faster heart rate , longer QRS duration ) , cardiac risk ( smoking , hypertension , prior cerebrovascular disease ) , and arrhythmia were important predictors of death between 30 days and 1 year . Black race was associated with a substantial increase in risk after considering other factors . Revascularization was associated with reduced risk between 30 days and 1 year . CONCLUSIONS When evaluating a patient who has survived acute infa rct ion treated with thrombolysis  , clinicians can estimate the likelihood of survival from factors easily measured during admission . Although many risk factors clearly relate to age , left ventricular dysfunction , or clinical instability , black race is an unexplained risk factor requiring further examination Summary In postmyocardial infa rct ion patients longterm aspirin treatment with 1.5 g/day led to a significant increase in systolic and diastolic blood pressure after 6 months . This could not be found in the placebo- and the phenprocoumon-treated patients . After one year the blood pressure behaviour was the same in all three treatment groups . As nonsteroidal antirheumatic drugs can produce hypertension in animals , probably due to inhibition of prostagl and in synthesis , blood pressure control in longterm aspirin treatment is advisable . ZusammenfassungNach 6 Monaten Therapie mit 1,5 g Acetylsalizylsäure täglich wurde bei Postinfarkt-Patienten ein signifikanter Anstieg des systolischen und diastolischen Blutdrucks beobachtet . Ein solches Ansteigen des Blutdrucks konnte bei den mit Placebo oder Phenprocoumon Beh and elten nicht nachgewiesen werden . Ein Jahr nach Therapiebeginn war das Blutdruckverhalten gleich in allen drei Therapiegruppen . Da auch bei Tieren mit nichtsteroidalen Antirheumatika ein Hochdruck erzeugt werden konnte , wahrscheinlich durch Hemmung der Prostagl and insynthese , ist die regelmäßige Blutdruckkontrolle während einer Langzeit-Aspirin-Therapie ratsam Arthritis and hypertension are frequent comorbidities in the elderly hypertensive population .  Nonsteroidal anti-inflammatory drugs are often used to relieve pain in arthritic patients but a side effect is sodium retention and consequent elevation of blood pressure ( BP ) . The effect of dihydropyridine calcium blocking drugs is relatively independent of sodium intake , whereas the angiotensin-converting enzyme ( ACE ) inhibitors ' effects can be blunted by a high-sodium diet . This study compared the effects of indomethacin with placebo in elderly patients with essential hypertension who had been controlled with amlodipine or enalapril . Indomethacin 50 mg twice daily or placebo was administered for 3 weeks in a double-blind crossover study to patients controlled with amlodipine or enalapril . The response was assessed by ambulatory BP measurement .  Indomethacin  raised BP and lowered pulse rates in patients taking enalapril but had little effect in patients receiving amlodipine . The difference caused by indomethacin between the two groups was 10.1/4.9 mm Hg increase in BP and a 5.6 beats/min fall in pulse in people taking enalapril . Addition of indomethacin to patients taking either drug caused a rise in weight and a fall in plasma renin . It is postulated that the effect is due to inhibition of prostagl and in synthesis , which causes sodium retention . In patients taking amlodipine , the fall in plasma renin ameliorates the effect of sodium retention on BP . In patients taking enalapril , plasma renin falls but this is not translated into an effect because of the blockage of converting enzyme . Thus , the full effect of sodium retention on BP is expressed . In patients treated with indomethacin , fewer patients may respond to ACE inhibitors . However , the major problem is the patient who intermittently takes indomethacin or other nonsteroidal anti-inflammatory drugs , which , if a person is treated by an ACE inhibitor causes BP to go out of control . In such patients amlodipine would appear to be a preferred choice to enalapril Background After coronary artery bypass surgery , patients have a high cumulative rate of graft closure and recurrent ischemic events . We sought to determine whether antiplatelet therapy with clopidogrel would be more effective than aspirin , the accepted st and ard , in these patients . Methods and Results The event rates for all-cause mortality , vascular death , myocardial infa rct ion , stroke , and rehospitalization were determined for the 1480 patients with a history of cardiac surgery r and omized to either clopidogrel or aspirin in a trial of 19 185 patients . The event rate per year of vascular death , myocardial infa rct ion , stroke , or rehospitalization was 22.3 % in the 705 patients r and omized to aspirin and 15.9 % in the 775 patients r and omized to clopidogrel ( P = 0.001 ) . A risk reduction was also seen in each of the individual end points examined , including a 42.8 % relative risk reduction in vascular death in patients on clopidogrel versus aspirin ( P = 0.030 ) . In a multivariate model incorporating baseline clinical characteristics , clopidogrel therapy was independently associated with a decrease in vascular death , myocardial infa rct ion , stroke , or rehospitalization in patients with a history of cardiac surgery , with a 31.2 % relative risk reduction ( 95 % CI , 15.8 to 43.8;P = 0.0003 ) . Although clopidogrel therapy was efficacious in the entire Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events ( CAPRIE ) population , multivariate analysis demonstrated that patients with previous cardiac surgery derived particular benefit ( P = 0.015 ) . Conclusion Compared with aspirin , clopidogrel therapy results in a striking reduction in the elevated risk for recurrent ischemic events seen in patients with a history of prior cardiac surgery , along with a decreased risk of bleeding Background — Patients with a non – ST-elevation acute coronary syndrome and prior CABG are at high risk of a recurrent ischemic event despite aspirin therapy . This trial investigated the potential benefit of secondary prevention with warfarin . Methods and Results —In a double-blind r and omized trial , 135 patients with unstable angina or non – ST-segment elevation myocardial infa rct ion , with prior CABG , and who were poor c and i date s for a revascularization procedure received therapy with aspirin and placebo+warfarin , warfarin and placebo+aspirin , or aspirin and warfarin for 12 months . Warfarin was titrated to an international normalized ratio of 2.0 to 2.5 . The primary end point ( death or myocardial infa rct ion or unstable angina requiring hospitalization 1 year after r and omization ) occurred in 14.6 % of the patients in the warfarin-alone group , in 11.5 % of patients in the aspirin-alone group , and in 11.3 % of patients r and omized to the combination therapy ( P = 0.76 ) . Subgroup analyses by risk features provided no indications that warfarin alone or in combination with aspirin could be of benefit over aspirin alone . Bleeding was more frequent in the 2 groups of patients administered warfarin . Conclusions —Moderate-intensity oral anticoagulation alone or combined with low-dose aspirin does not appear to be superior to low-dose aspirin in the prevention of recurrent ischemic events in patients with non – ST-elevation acute coronary syndromes and previous CABG This study investigates the possible effects of acetylsalicylic acid ( ASA ; aspirin ) on systolic ( S ) and diastolic ( D ) blood pressure ( BP ) in healthy and mildly hypertensive subjects receiving ASA at different times according to their rest-activity cycle . A double-blind , r and omized , controlled trial was conducted in 73 healthy young adult volunteers and 18 previously untreated subjects with mild hypertension . The BP of each subject was automatically monitored every 30 minutes for 48h before the trial and at the end of a one-week course of placebo and a one-week course of ASA .  Healthy volunteers were r and omly assigned to one of six groups , defined according to the dose of ASA ( either 500 mg/day , the usual commercial dose ; or 100 mg/day ) and timing of ASA and placebo ( within 2h after awakening , Time 1 ; 7h to 9h after awakening , Time 2 ; or within 2h of bedtime , Time 3 ) . Subjects with mild hypertension received the low dose of 100 mg/day ASA , as well as one week of placebo , and were r and omly assigned to one of the same three groups defined above according to the time of treatment . A small ( approximately 2 mmHg in the 24h mean of SBP ) , but statistically significant , BP reduction was found when 500 mg/day ASA was given to healthy volunteers at Time 2 . With 100 mg/day , the effect of ASA in healthy subjects was comparable to the BP reduction found with the higher dose for Time 2 ; there was again no effect on BP at Time 1 , but we found a statistically significant effect at Time 3 ( 2.3 mmHg reduction in the 24h mean of SBP ) , larger than for Time 2 . For hypertensive patients , the BP reduction was again statistically significant for Time 2 and , to a greater extent , for Time 3 ( approximately 4.5 mmHg for both SBP and DBP ) ; all patients in these two groups showed a BP reduction after one week of ASA . The effect was about three times as large as the BP reduction obtained in healthy subjects treated with 100 mg/day ASA . Results indicate a statistically significant time- and dose-dependent effect of ASA on BP . In any meta- analysis of ASA effects , inquiries about the time when subjects took the drug are indicated and may account for discrepancies in the literature . Moreover , the influence of ASA on BP demonstrated here indicates the need to identify and control for ASA effects in patients using  ASA  before and during their participation in antihypertension medication trials OBJECTIVE Nonsteroidal antiinflammatory drugs ( NSAID ) have been associated with hemodynamically mediated acute renal failure .  There appear to be differences among NSAID in producing this effect . We compare renal effects of ibuprofen , sulindac , and nabumetone . METHODS Seventeen women over age 56 receiving hydrochlorothiazide and fosinopril for hypertension who had osteoarthritis requiring NSAID received 3 different NSAID to evaluate potential varying renal effects . In an investigator blinded r and omized study , patients received nabumetone , sulindac , or ibuprofen for 1 month with intervening 2 week control periods . After each period renal function was assessed by inulin and para-aminohippurate clearances and urinary prostagl and ins were measured . RESULTS No overall statistical differences among the NSAID were observed . However , there were clinical ly meaningful differences during ibuprofen therapy : 4 patients developed a clinical ly significant decrease in renal function ; during sulindac therapy one of these also developed a clinical ly significant decrease in renal function . During nabumetone there were 0 episodes of clinical ly significant decrease in renal function . Using Gomez equations , glomerular hydrostatic pressure and afferent and efferent arteriolar resistances were estimated . None changed overall during any intervention . However , the 4 patients who developed decreased renal function while taking ibuprofen were analyzed separately . Glomerular hydrostatic pressure decreased 15 % ; afferent arteriolar resistance increased 85 % . These changes were associated with marked decreases in vasodilatory prostagl and ins compared to patients receiving ibuprofen who did not develop decreases in renal function . CONCLUSION There are differences in effect on renal function among NSAID . These can be correlated with specific alterations in suppression of the cyclooxygenase system cascade and related to changes in the hemodynamic control of glomerular filtration BACKGROUND Nonsteroidal anti-inflammatory drugs may attenuate the antihypertensive effects of diuretics , beta-blockers , angiotensin-converting enzyme inhibitors , central alpha-agonists , and other vasodilators . Their effects on the antihypertensive efficacy of calcium channel blockers are inadequately studied in small numbers of patients but appear to be minimal . METHODS A three-phase , r and omized , double-blind , placebo-controlled  multicenter study included 162 patients aged 18 to 75 years with essential hypertension . After diastolic blood pressure was controlled to 90 mm Hg or less with once-daily verapamil hydrochloride , patients received ibuprofen , naproxen , or placebo matching capsules for 3 weeks , and blood pressure , heart rate , weight , and adverse effects were evaluated . A general linear model with 95 % confidence intervals was used to compare each nonsteroidal anti-inflammatory drug treatment group with the placebo group . RESULTS No significant differences in sitting , st and ing , or supine blood pressure were noted with naproxen or ibuprofen compared with placebo . The percentages of patients in each treatment group with increases of 10 mm Hg or more in either systolic or diastolic blood pressure were similar . Statistically significant increases in weight were seen with both nonsteroidal anti-inflammatory drug therapies . Changes in pulse rate were not significant . The incidence of adverse effects was similar across all three treatment groups . CONCLUSIONS The addition of naproxen or ibuprofen to the treatment of hypertensive patients in whom blood pressure is controlled by once-daily verapamil does not cause an increase in blood pressure .  Verapamil may therefore offer considerable advantages in maintaining control of blood pressure in patients who regularly receive nonsteroidal anti-inflammatory drug therapy 1 . The effects of non-steroidal anti-inflammatory drugs ( NSAID ) on prostacyclin and thromboxane bio synthesis and on blood pressure were determined in 46 patients with mild essential hypertension . Patients who had abstained from antihypertensive therapy for 2 weeks before study were treated with either aspirin , ibuprofen , sulindac or placebo for 7 days . 2 . Excretion rates of 2,3-dinor-6-oxo-prostagl and in ( PG ) F1 alpha , 6-oxo-PGF1 alpha , 2,3-dinorthromboxane ( TX ) B2 and TXB2 were measured as indices of prostacyclin and TXA2 bio synthesis . Sample s were assayed using immunoaffinity chromatography and gas chromatography/electron capture chemical ionisation mass spectrometry . 3 . Aspirin and ibuprofen reduced urinary excretion of all prostacyclin- and thromboxane-derived products . Sulindac inhibited excretion of 2,3-dinor-6-oxo-PGF1 alpha , 6-oxo-PGF1 alpha and 2,3-dinor-TXB2 , but had no significant effect on TXB2 . 4 . Systolic blood pressure increased in the ibuprofen-treated group when compared with the placebo group . There were no other significant changes in systolic or diastolic pressure in any of the treatment groups . Among the patients as a whole , there was a significant negative correlation between change in blood pressure and change in excretion of the prostacyclin-derived but not of the thromboxane-derived products . 5 . We conclude that , in patients with mild essential hypertension , neither sulindac nor aspirin ( in the doses used ) selectively spares prostacyclin bio synthesis by the kidney . The significant relationship between increase in blood pressure and reduction in prostacyclin bio synthesis favours the possibility that in individuals who become hypertensive , prostacyclin bio synthesis determines , in part , the severity of the hypertensive state BACKGROUND An inverse association between moderate alcohol consumption and  coronary heart disease ( CHD ) has been observed in several epidemiological studies . To assess whether a similar association exists among diabetics , we examined the relation between light to moderate alcohol consumption and CHD in men with and without diabetes mellitus in a prospect i ve cohort study . METHODS AND RESULTS A total of 87 938 US physicians ( 2790 with diagnosed diabetes mellitus ) who were invited to participate in the Physicians ' Health Study and were free of myocardial infa rct ion , stroke , cancer , or liver disease at baseline were followed for an average of 5.5 years for death with CHD as the underlying cause . During 480 876 person-years of follow-up , 850 deaths caused by CHD were documented : 717 deaths among nondiabetic men and 133 deaths among diabetic men . Among men without diabetes at baseline , the relative risk estimates for those reporting rarely/never , monthly , weekly , and daily alcohol consumption were 1.00 ( referent ) , 1.02 , 0 . 82 , and 0.61 ( 95 % CI 0.49 to 0.78 ; P for trend < 0.0001 ) after adjustment for age , aspirin use , smoking , physical activity , body mass index , and history of angina , hypertension , and high cholesterol . Among men with diabetes at baseline , the relative risk estimates were 1.00 ( referent ) , 1.11 , 0.67 , and 0.42 ( 95 % CI 0.23 to 0.77 ; P for trend=0.0019 ) . CONCLUSIONS These results suggest that light to moderate alcohol consumption is associated with similar risk reductions in CHD among diabetic and nondiabetic men The benefit of aspirin therapy among women with coronary artery disease ( CAD ) is not well established . Previous studies have shown conflicting results among women . Data from 2,418 women with CAD screened for participation in the ongoing Bezafibrate Infa rct ion Prevention ( BIP ) study were analyzed : 45 % reported aspirin therapy . Baseline characteristics were similar in both groups . Cardiovascular mortality at 3.1 + /- 0.9 years of follow-up was 2.7 % in the aspirin treated group versus 5.1 % in the non-aspirin-treated women ( p = 0.002 ) . All cause mortality was 5.1 % and 9.1 % , respectively ( p = 0.0001 ) . Treatment with aspirin emerged as an independent predictor of reduced cardiovascular ( RR = 0.61 , 95 % confidence interval [ CI ] 0.38 to 0.97 ) and all cause ( RR = 0.66 , 95 % CI 0.47 to 0.93 ) mortality after multiple adjustment for possible confounders such as age , history of myocardial infa rct ion , systemic hypertension , diabetes mellitus , peripheral vascular disease , current smoking , New York Heart Association classification , and concomitant treatment with digitalis . Women who benefited the most from aspirin therapy were older , diabetic , symptomatic , or had a previous myocardial infa rct ion . Thus , treatment with aspirin was associated with reduced mortality among women with CAD . This study suggests that women with CAD should be treated with aspirin , unless specific contraindications exist Objective The objective of this study was to provide a comprehensive comparison of the long term safety and tolerability of clopidogrel , a new adenosine diphosphate ( ADP ) receptor antagonist that inhibits platelet activation induced by ADP , and aspirin ( acetylsalicylic acid ) . Patients and Methods The study population comprised 19 185 patients with symptomatic atherosclerosis manifested as recent ischaemic stroke , recent myocardial infa rct ion or symptomatic peripheral arterial disease . Patients were r and omised to receive  clopidogrel 75 mg/day or aspirin 325 mg/day  for a minimum of 1 year and a maximum of 3 years . Results Compared with aspirin , clopidogrel reduced the combined risk of ischaemic stroke , myocardial infa rct ion or vascular death by 8.7 % ( p = 0.043 ) . The incidence of early permanent discontinuations of the study drug due to adverse events was almost identical in both treatment groups ( 11.94 % for clopidogrel vs 11.92 % for aspirin ) . Reported neutropenia was similar in the clopidogrel and aspirin groups ( 0.10 vs 0.17 % , respectively ) with corresponding rates ( 0.05 vs 0.04 % , respectively ) for severe neutropenia . Thrombocytopenia was identical in the clopidogrel and aspirin groups ( 0.26 % ) , with the rates of severe thrombocytopenia being 0.19 vs 0.10 % , respectively . None of these observed differences was statistically significant . The overall incidence of haemorrhagic events did not differ statistically significantly between treatment groups ( 9.27 % for clopidogrel vs 9.28 % for aspirin ; p = 0.98 ) . There was a trend towards a lower incidence of intracranial haemorrhage in the clopidogrel group ( 0.31 % ) compared with the aspirin group ( 0.42 % ) . Any reported gastrointestinal haemorrhage was significantly less frequent with clopidogrel ( 1.99 % ) than with aspirin ( 2.66 % ) [ p < 0.002 ] . The corresponding data for severe gastrointestinal bleeding were 0.49 vs 0.71 % ; p < 0.05 . Overall , there were significantly fewer gastrointestinal adverse events with clopidogrel than with aspirin ( 27.1 vs 29.8 % ; p < 0.001 ) , with less abdominal pain , dyspepsia , constipation , or peptic , gastric , or duodenal ulceration with clopidogrel .  Diarrhoea was significantly more common in the clopidogrel group ( 4.46 vs 3.36 % ; p < 0.001 ) , although the incidence of severe diarrhoea ( 0.23 vs 0.11 % ) was low and was not significantly different between groups . There were significantly more patients with rash in the clopidogrel group ( 6.0 % ) compared with the aspirin group ( 4.6 % ) [ p < 0.001 ] . However , these events were generally mild and transient in nature . Conclusion Given the favourable benefit/risk ratio , clopidogrel represents a clinical ly important advance in the treatment of patients with manifest atherosclerotic disease Nonsteroidal antiinflammatory drugs ( NSAID ) are frequently reported to interfere with the blood pressure lowering actions of various antihypertensive medications . We studied 17 women with arthritis and hypertension who were receiving fosinopril and HCTZ  , and administered sequentially in r and om order ibuprofen , sulindac , and nabumetone for 1 month each , with an intervening 2-week washout period between each treatment period . During the washout period , subjects received acetaminophen .  Blood pressure at the end of 2 weeks of acetaminophen was compared with blood pressure after 1 month of treatment with each of the NSAID . Mean blood pressure was unchanged before and after all NSAID : 108 + /- 7 v 107 + /- 9 for nabumetone , 108 + /-9 v 108 + /- 9 for sulindac , and 108 + /- 8 v 107 + /- 9 for ibuprofen . The 24-h urinary sodium excretion was not significantly different . We conclude that the three NSAID did not neutralize the antihypertensive effect of the combination of fosinopril and HCTZ , and hence the blood pressure lowering action of the combination may not be prostagl and in dependent Aspirin is only modestly effective in the secondary prevention after cerebral ischemia . Studies in other vascular disorders suggest that anticoagulant drugs in patients with cerebral ischemia of presumed arterial ( noncardiac ) origin might be more effective . The aim of the Stroke Prevention in Reversible Ischemia Trial ( SPIRIT ) therefore was to compare the efficacy and safety of 30 mg aspirin daily and oral anticoagulation ( international normalized ratio [ INR ] 3.0–4.5 ) . Patients referred to a neurologist in one of 58 collaborating centers because of a transient ischemic attack or minor ischemic stroke ( Rankin grade $ 3 ) were eligible . R and omization was concealed , treatment assignment was open , and assessment of outcome events was masked . The primary measure of outcome was the composite event “ death from all vascular causes , nonfatal stroke , nonfatal myocardial infa rct ion , or nonfatal major bleeding complication . ” The trial was stopped at the first interim analysis . A total of 1,316 patients participated ; their mean follow‐up was 14 months . There was an excess of the primary outcome event in the anticoagulated group ( 81 of 651 ) versus 36 of 665 in the aspirin group ( hazard ratio , 2.3 ; 95 % confidence interval [ CI ] , 1.6–3.5 ) . This excess could be attributed to 53 major bleeding complications ( 27 intracranial ; 17 fatal ) during anticoagulant therapy versus 6 on aspirin ( 3 intracranial ; 1 fatal ) . The bleeding incidence increased by a factor of 1.43 ( 95 % CI , 0.96–2.13 ) for each 0.5 unit increase of the achieved INR . Anticoagulant therapy with an INR range of 3.0 to 4.5 in patients after cerebral ischemia of presumed arterial origin is not safe . The efficacy of a lower intensity anticoagulation regimen remains to be determined From 1979 - 85 , 2435 patients with a transient ischaemic attack or minor ischaemic stroke were r and omly allocated to receive long term " blind " treatment with aspirin 600 mg twice daily ( n = 815 ) , aspirin 300 mg once daily ( n = 806 ) or placebo ( n = 814 ) . No patient was lost to follow up . The " intention to treat " comparison included all the serious vascular events and deaths which occurred before the end of the follow up period on 30 September 1986 . There was no difference in efficacy between the 300 mg and 1200 mg daily doses of aspirin , but the lower dose was undoubtedly less gastrotoxic . Also , there was no definite difference in the response of  males and females to aspirin . The odds of suffering a major stroke , myocardial infa rct ion or vascular death were 15 % less in the combined aspirin groups compared with the placebo group ( 95 % confidence interval 29 % reduction to 3 % increase in odds ) which is compatible with the continuing overview of all the similar trials of antiplatelet drugs where the relative reduction in odds was 25 % . There was no statistically significant reduction in the likelihood of either disabling major stroke and vascular death or vascular death occurring Effect of non-steroidal anti-inflammatory drug ( NSAID ) on blood pressure ( BP ) control was evaluated in elderly hypertensive patients treated with calcium antagonist .  The study was based on a r and omized , crossover design to compare the effect of an NSAID , sulindac , with that of another NSAID , diclofenac sodium , in the hypertension treatment . The study was completed in six elderly female subjects ( the average age : 66 + /- 3 year ) whose systolic BP and diastolic BP were more than 160 mmHg and more than 95 mmHg , respectively . When BP was controlled by nifedipine ( 20 mg x 2 per day in slow releasing form ) within normal limits , sulindac ( 100 mg x 3 per day ) or diclofenac sodium ( 25 mg x 3 per day ) was administered for a week . After one week-washout period , the other NSAID was substituted . Plasma and urinary variables were measured on the final day of each study period . The average systolic BP and diastolic BP and the entry of study were 167 + /- 5 mmHg and 93 + /- 5 mmHg , respectively . Nifedipine significantly decreased the systolic BP to 140 + /- 4 mmHg ( p less than 0.02 ) and the diastolic BP to 84 + /- 4 mmHg ( p less than 0.05 ) . Addition of either sulindac or diclofenac sodium did not affect BP , whereas urinary PGE2 excretion and plasma renin activity were significantly inhibited . Plasma creatinine and electrolyte concentration were not changed by the NSAIDs . The results indicate that either sulindac or diclofenac sodium does not interfere with control of hypertension by a calcium antagonist , nifedipine in in elderly hypertensive patients . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND In a retrospective study , antiplatelet therapy has been shown to be associated with a decreased incidence of erythropoietin-induced hypertension . In order to ascertain the role of antiplatelet drugs in the haemodynamic response to the correction of anaemia by rHuEpo , 18 patients on chronic haemodialysis who started rHuEpo therapy  were prospect ively studied . METHODS The subjects were r and omly assigned to receive or not , one of the following antiplatelet drugs : ditazole ( 3 patients ) , ticlopidine ( 3 patients ) or aspirin plus dipyridamole ( 3 patients ) . Cardiac index ( CI ) by echo-Doppler , total peripheral resistance ( TPR ) and mean arterial pressure ( MAP ) were determined at baseline 10 and 20 weeks following the initiation of rHuEpo therapy . rHuEpo therapy was administered subcutaneously at the same dose ( 40 U/kg thrice weekly ) during the first 10 weeks . Ten uraemic patients on haemodialysis who had never received rHuEpo therapy served as the control group . RESULTS One patient in the group without antiplatelet drugs discontinued the study due to the development of severe hypertension after 12 weeks on rHuEpo therapy . There were no significant differences in the haemodynamic parameters at baseline . At 10 weeks , MAP was higher in patients without than with antiplatelet drugs or controls untreated with rHuEpo ( 128.5 + /- 28 versus 100.6 + /- 13.5 versus 98.7 + /- 14 mmHg respectively , P = 0.0047 ) , TPR was also higher in patients without antiplatelet drugs than in the 2 other groups ( 1919 + /- 433 versus 1576 + /- 359 versus 1418 + /- 324 din.seg.cm-5m2 respectively , P = 0.0231 ) , but CI did not differ among the three groups . At 20 weeks , MAP was still higher in patients without antiplatelet drugs than in patients with antiplatelet drugs or controls not on rHuEpo therapy respectively ( 112.9 + /- 24.6 versus 91.0 + /- 9.0 versus 101.7 + /- 14.1 mmHg respectively , P = 0.075 ) , but at this stage TPR and Cl did not differ among the three groups . CONCLUSIONS These data reinforce the previous observation that antiplatelet therapy may prevent the development of rHuEpo-induced hypertension The Coumadin Aspirin Reinfa rct ion Study demonstrated that combination treatment with fixed dose warfarin ( 1 or 3 mg ) + aspirin 80 mg was not superior to aspirin 160 mg alone after myocardial infa rct ion for reducing nonfatal reinfa rct ion , nonfatal stroke , and cardiovascular death . In this analysis , we examined the importance of aspirin dose in the protection against the secondary end point of ischemic stroke . The comparison arms for this analysis were warfarin 1 mg + aspirin 80 mg versus aspirin 160 mg . In the Coumadin Aspirin Reinfa rct ion Study , 2,028 patients were r and omized to aspirin 80 mg plus warfarin 1 mg , and 3,393 were r and omized to aspirin 160 mg alone . A predictive model for ischemic stroke was developed using the Cox proportional-hazards model . A reduced Cox proportional-hazards model was developed to test for the effect of aspirin dose on ischemic stroke in predefined subgroups . The incidence of ischemic stroke was lower in patients treated with aspirin  160 mg than in patients treated with aspirin 80 mg + warfarin 1 mg ( 0.6 % vs 1.1 % ; p = 0.0534 ) . Age , previous stroke or transient ischemic attack , and aspirin dose were independent predictors of ischemic stroke . In addition , the highest risk patients , those with Q-wave myocardial infa rct ion and male patients , appeared to receive greater benefit from aspirin 160 mg than from aspirin 80 mg + warfarin 1 mg . The results of this secondary analysis suggest that aspirin 160 mg is more effective than aspirin 80 mg + warfarin 1 mg in preventing ischemic stroke in post-myocardial infa rct ion patients To determine whether endothelin-1 ( ET-1 ) contributes to hypertension associated with non-steroidal anti-inflammatory drug ( NSAID ) usage in healthy , elderly , normotensive individuals a r and omised , double-blind , placebo-controlled , crossover trial of indomethacin was undertaken in 41 healthy , elderly individuals with stable normotension or controlled hypertension ( blood pressure ( BP ) < or = 160/90 mm Hg ) . The main outcome measures were systolic and diastolic BP , heart rate , cardiac output , weight , creatinine clearance , plasma renin activity , aldosterone , endothelin-1 and arginine vasopressin concentrations and 24 h urinary endothelin-1 and 6 keto prostagl and in F1 alpha outputs . Analysis of covariance was used to evaluate the effect of indomethacin on BP and related parameters . Indomethacin treatment for 1 month increased systolic ( + /- s.e.m . : 4.1 + /- 2.2 mm Hg ; 95 % confidence interval 0 to 8.3 mm Hg ) and diastolic BP ( 2.7 + /- 1.1 mm Hg ; 0.4 to 4.9 mm Hg ) without altering cardiac output ( P = 0.59 ) , implying an increase in total peripheral resistance .  Indomethacin treatment produced a small increase in weight ( 1.4 + /- 0.4 kg ; 0.6 to 2.2 kg ) , a small reduction in renal function ( creatinine clearance : 6.8 + /- 1.8 mis/min ; 3.3 to 10.3 mis/min ) but a significant ( 83 % ) increase in daily urinary endothelin-1 production ( 13.1 + /- 3.4 ng/ml ; 6.4 to 19.8 ng/ml ) without altering plasma ET-1 concentration , suggesting increased renal synthesis . In conclusion , renal paracrine effects of ET-1 may contribute to NSAID-induced blood pressure elevation in humans Objective : To assess the relationship between chronic intake of nonsteroidal anti-inflammatory drugs ( NSAID ) and outcome , in particular ( gastrointestinal ) bleeding and to investigate whether the effect of chronic NSAID intake was similar in untreated and treated elderly hypertensives . Methods : Eligible patients ( ⩾60 years , with systolic blood pressure 160–219 mm Hg and diastolic blood pressure < 95 mm Hg ) were r and omised to active treatment or placebo . Active treatment consisted of nitrendipine , with the possible addition of enalapril , hydrochlorothiazide , or both , titrated or combined to reduce the sitting systolic blood pressure by at least 20 mm Hg to below 150 mm Hg . Patients never taking NSAIDs ( n = 2882 ) were compared with patients on chronic NSAID intake ( n= 861 ) , defined as reporting NSAID intake on at least 50 % of the patient forms . Results : There was a tendency towards lower mortality ( relative hazard rate ( 95 % confidence interval ( CI ) , 0.77 ( 0.56–1.06 ) ) and higher incidence of bleeding ( 1.13 ( 0.63–2.05 ) with chronic NSAID intake . Although there was no significant interaction between calcium-channel blocker (CCB)-based treatment and chronic NSAID intake for any of the end points , chronic NSAID intake tended to be associated with a lower incidence of bleeding on active treatment as compared to placebo ( P-value of the interaction term = 0.07 ) . Conclusion : The effect of chronic NSAID intake on outcome was similar in patients on active treatment based on a dihydropyridine CCB or on placebo . However , chronic NSAID intake might have a less deleterious effect on bleeding on active treatment as compared to placebo BACKGROUND When administered intravenously at the time of percutaneous coronary revascularization , glycoprotein IIb/IIIa receptor antagonists decrease the incidence of death and nonfatal myocardial infa rct ion and the need for urgent revascularization . We hypothesized that long-term administration of oral glycoprotein IIb/IIIa antagonists , which block the aggregation of platelets , might stabilize intravascular plaque and prevent additional ischemic cardiac events . METHODS We conducted a prospect i ve , double-blind trial in which 7232 patients were r and omly assigned to receive 20 mg of oral xemilofiban or placebo 30 to 90 minutes before undergoing percutaneous coronary revascularization , with maintenance doses of 10 or 20 mg of xemilofiban or placebo administered three times daily for up to 182 days . There were two primary composite end points : one was death , nonfatal myocardial infa rct ion , or urgent revascularization at 182 days , and the other was death or nonfatal myocardial infa rct ion at 182 days . RESULTS Death , myocardial infa rct ion , or urgent revascularization occurred within 182 days in 324 patients who received  placebo  ( Kaplan-Meier cumulative event rate , 13.5 percent ) , 332 who received 10 mg of xemilofiban ( 13.9 percent , P=0.82 for the comparison with placebo ) , and 306 who received 20 mg of xemilofiban ( 12.7 percent , P=0.36 for the comparison with placebo ) . The incidence of death or myocardial infa rct ion was also similar in all three groups . Clinical ly significant hemorrhagic complications and thrombocytopenia were infrequent . CONCLUSIONS The administration of the glycoprotein IIb/IIIa antagonist xemilofiban before percutaneous coronary revascularization and for up to six months thereafter does not significantly reduce the incidence of important clinical end points OBJECTIVE To evaluate in hypertensive patients whether or not the sodium-retaining effects of indomethacin can explain the indomethacin-induced attenuation of enalapril antihypertensive effects . DESIGN R and omized , single-blinded , placebo controlled study with a placebo phase ( 2 weeks ) followed by enalapril 20 mg/d ( 4 weeks , once daily ) and enalapril 20 mg + indomethacin 75 mg/d ( 1 week ) . Enalapril dose increased up to 40 mg/d if inadequate response to 20 mg . PATIENTS Twenty-four patients with mild-moderated hypertension , showing an adequate response to enalapril ( 20 - 40 mg/d ) . METHODS Blood pressure evaluated by " casual " methods and by 24-hour ambulatory blood pressure monitoring , measurement of 24-hour urinary sodium excretion and fractional excretion of sodium : at the end of placebo , enalapril and enalapril + indomethacin treatments . Determination of the correlations between the changes induced by indomethacin ( when added to enalapril ) on the blood pressure and on sodium excretion effects of enalapril . RESULTS Enalapril significantly reduced casual blood pressure ( systolic/diastolic ) by 33/18 mmHg and 24-hour blood pressure by 20/9 mmHg . When added to enalapril , indomethacin attenuated ( by 50 % ) the antihypertensive effects of enalapril and significantly decreased the 24-hour ( from 120 + /- 11 mmol to 106 + /- 10 mmol ) and fractional excretion of sodium ( from 1.11 + /- 0.09 % to 0.75 + /- 0.06 % ) . However , the indomethacin-induced attenuation of enalapril hypotensive effects did not correlate with indomethacin-induced changes of sodium excretion . CONCLUSIONS When indomethacin is administrated to hypertensive patients that are well controlled with enalapril , it produces a marked attenuation of enalapril hypotensive effects and produces sodium retention . However , the amount of the attenuation of the hypotensive effects of enalapril by indomethacin are completely independent of the amount of the indomethacin-induced sodium retention . These results suggest that the mechanisms involved in interaction between both drugs at the blood pressure domain are probably localized at an extra-renal level To determine the renovascular effects of nonprescription ibuprofen in the maximum labeled over-the-counter ( OTC ) dosage for 7 days , and to compare these effects with those of two other available OTC analgesics , aspirin and acetaminophen , we evaluated 25 elderly patients with mild thiazide-treated hypertension and mild renal insufficiency . Under double-blind conditions , patients were r and omly allocated to one of three treatment groups : ibuprofen 400 mg 3 times/day , aspirin 650 mg 3 times/day , or acetaminophen 650 mg 3 times/day . Blood pressure and indexes of renal function ( blood urea nitrogen , creatinine clearance , serum electrolytes ) were measured over 7 days in a clinical research center . None of the treatments had a clinical ly significant effect on blood pressure . Renal function indexes also remained unchanged during all three treatments . We conclude that elderly patients with mild thiazide-treated hypertension and mild renal insufficiency seem not to be at risk of developing additional renal compromise or of having their hypertension control diminished by treatment with these OTC analgesics for 7 days OBJECTIVE To determine whether a regimen of methotrexate , cyclosporin A , and corticosteroids introduced at onset in poor-prognosis rheumatoid arthritis ( RA ) can produce a significant improvement in outcome compared with st and ard monotherapy with sulfasalazine ( SSZ ) . METHODS Eighty-two consecutive patients presenting with new , untreated RA of less than 12 months ' duration who fulfilled criteria for poor long-term outcome were r and omized to receive either combination therapy ( n = 40 ) or SSZ alone ( n = 42 ) . The primary outcome measures were remission and American College of Rheumatology ( ACR ) criteria for 20 % improvement at 48 weeks . RESULTS After 48 weeks , the numbers of patients who met the ACR criteria for 20 % improvement were not significantly different between the two groups ( combination 58 % versus SSZ 45 % ) , and similar numbers of patients had persisting clinical remission ( approximately 10 % both groups ) . During the first 3 months , there were significantly greater reductions in parameters of disease activity in the combination group . By 24 weeks , the swollen and tender joint counts , C-reactive protein levels , and erythrocyte sedimentation rates had fallen significantly in both groups , with a greater improvement in the swollen and tender joint count in the combination group . At 48 weeks , the radiographic damage score had increased by a median of 1 ( range 0 - 42.5 ) in the combination group and 1.25 ( range 0 - 72.5 ) in the SSZ group ( P = 0.28 ; although there were significant differences in the scores for the right h and ) . There were significantly fewer withdrawals due to lack of efficacy in the combination group than in the SSZ group ( 1 of 40 versus 10 of 42 ; P = 0.007 ) . In the combination group , dose reduction was needed in 22.5 % because of hypertension and in 22.5 % because of elevated creatinine levels . Over 48 weeks , serum creatinine increased in both groups , but particularly in the combination arm . CONCLUSION In poor-prognosis RA patients , " aggressive " combination therapy led to more rapid disease suppression but did not result in significantly better ACR response or remission rates . This suggests that in poor-prognosis disease , an approach based on identifying patients with poor treatment responses before extra therapy is added ( " step-up " approach ) may be more appropriate than the use of combination therapy in all patients from the outset We performed a subgroup analysis of the first European Stroke Prevention Study including 1,306 patients recruited in a single center , Kuopio , Finl and , to investigate whether or not antiplatelet therapy is effective in the secondary prevention of stroke in hypertensive patients with transient ischemic attack ( TIA ) or stroke . The patients were treated with aspirin , 990 mg/day , plus dipyridamole , 225 mg/day , or placebo for 2 years . The patients with high systolic blood pressure ( > or = 140 mm Hg ; n = 1.105 ) or high diastolic blood pressure ( > or = 85 mm Hg ; n = 1,120 ) at entry , were classified into subgroups by blood pressure level . The effect of treatment was statistically significant in all subgroups with high systolic ( end-point reduction , 55.2 - 68.2 % ) and diastolic blood pressure ( end-point reduction , 47.3 - 82.1 % ) . Risk reduction was , however , greatest in patients with the highest diastolic blood pressure . One possible explanation is that platelets are more activated in these patients , and this can be effectively prevented by antiplatelet therapy . Further studies are needed to confirm this hypothesis Patients who had survived a stroke or transient ischaemic attacks ( TIA ) were admitted to a trial of low-dose aspirin ( 50 mg ) alone , sustained release dipyridamole ( 400 mg/day ) alone , or a combination of the two agents , and results compared with a placebo over 24 months . This low-dose aspirin regimen produced in pairwise comparisons a significant risk reduction of 18 % for stroke , 13 % for stroke and /or death but no reduction in all cause mortality . The sustained release dipyridamole produced a significant risk reduction of 16 % for stroke , 15 % for stroke and /or death but no significant reduction of mortality . In combination , aspirin and dipyridamole produced a risk reduction of 37 % in stroke , 24 % in stroke and /or death , and no reduction in mortality . Similar findings were found in TIA , which was a secondary endpoint . These results are highly significant in comparison with placebo . As expected , there were enhanced reports of alimentary side-effects in the aspirin groups and also enhanced bleeding .  Dipyridamole was associated with a slight increase in headache , which resolved in most patients if therapy was continued . The conclusions are that 50 mg/day of aspirin alone or 400 mg/day of sustained release dipyridamole alone are equally effective in stroke and TIA prevention . When used in combination the effects were additive and were significantly more effective than the single agents Objective : To evaluate the influence of non-steroidal anti-inflammatory drugs ( NSAIDs ; aspirin and indomethacin ) on the renal and antihypertensive effects of enalapril and nifedipine gastrointestinal therapeutic system ( GITS ) in patients with essential hypertension . Design and methods : In a crossover study , 18 patients on an unrestricted-salt diet were r and omly assigned to receive either enalapril ( 20 - 40 mg/day ) or nifedipine-GITS ( 30 - 60mg/day ) for 4 - 8 weeks , followed by aspirin ( 100 mg/day for 2 weeks ) and then indomethacin ( 75 mg/day for 1 week ) . Blood pressure was measured by 24 h ambulatory monitoring . Results : Enalapril and nifedipine-GITS significantly reduced blood pressure compared with placebo . Aspirin did not alter the antihypertensive effect of either drug . Indomethacin attenuated ( by 45 % ) the antihypertensive effect of enalapril throughout the 24 h period of evaluation , but did not interfere with the effect of nifedipine . Furthermore , indomethacin significantly reduced the fractional excretion of sodium and plasma levels of prostagl and ins in a similar way when added to either the enalapril or the nifedipine regimen . Conclusions : Vasodilatory prostagl and ins are probably involved in the antihypertensive effects of enalapril but not of nifedipine , and this interaction seems to be independent of any indomethacin-induced decrease in renal sodium excretion .  Nifedipine may be an appropriate drug to treat hypertensive patients requiring concomitant therapy with NSAID BACKGROUND Despite treatment , there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals . Inadequate reduction of their blood pressure is a likely cause , but the optimum target blood pressure is not known . The impact of acetylsalicylic acid ( aspirin ) has never been investigated in patients with hypertension . We aim ed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension . METHODS 18790 patients , from 26 countries , aged 50 - 80 years ( mean 61.5 years ) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg ( mean 105 mm Hg ) were r and omly assigned a target diastolic blood pressure . 6264 patients were allocated to the target pressure < or = 90 mm Hg , 6264 to < or = 85 mm Hg , and 6262 to < or = 80 mm Hg . Felodipine was given as baseline therapy with the addition of other agents , according to a five-step regimen . In addition , 9399 patients were r and omly assigned 75 mg/day acetylsalicylic acid ( Bamycor , Astra ) and 9391 patients were assigned  placebo . FINDINGS Diastolic blood pressure was reduced by 20.3 mm Hg , 22.3 mm Hg , and 24.3 mm Hg , in the < or = 90 mm Hg , < or = 85 mm Hg , and < or = 80 mm Hg target groups , respectively . The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg ; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg . Further reduction below these blood pressures was safe .  In patients with diabetes mellitus there was a 51 % reduction in major cardiovascular events in target group < or = 80 mm Hg compared with target group < or = 90 mm Hg ( p for trend=0.005 ) . Acetylsalicylic acid reduced major cardiovascular events by 15 % ( p=0.03 ) and all myocardial infa rct ion by 36 % ( p=0.002 ) , with no effect on stroke . There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group , and 129 versus 70 non-fatal major bleeds in the two groups , respectively ( p<0.001 ) . INTERPRETATION Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events . The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg . Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infa rct ion . There was no effect on the incidence of stroke or fatal bleeds , but non-fatal major bleeds were twice as common BACKGROUND Many trials in patients with acute myocardial infa rct ion have demonstrated that thrombolytic therapy is not associated with an excessive risk of stroke , as compared with conventional treatment . However , the incidence of various forms of stroke in patients treated with different thrombolytic and antithrombotic regimens  and the associated effect of risk factors for stroke are largely unknown . METHODS Strokes occurring in patients hospitalized with acute myocardial infa rct ion who were enrolled in either of two large trials were analyzed . The patients were r and omly assigned to receive streptokinase ( 1.5 million units ) or recombinant tissue plasminogen activator ( t-PA ) ( 100 mg ) and also r and omly assigned to receive subcutaneous heparin or no heparin . Ninety-one percent of the patients also received aspirin . RESULTS Complete data were available on 20,768 patients . A total of 236 ( 1.14 percent ) had strokes in the hospital ; 0.36 percent had hemorrhagic strokes , 0.48 percent ischemic strokes , and 0.30 percent strokes of undefined cause . Patients treated with t-PA had a small but significant excess of stroke as compared with those who received streptokinase ( 1.33 vs. 0.94 percent ; adjusted odds ratio , 1.42 ; 95 percent confidence interval , 1.09 to 1.84 ) . The administration of subcutaneous heparin in addition to a thrombolytic agent did not increase the risk of stroke ( risk with heparin , 1.13 percent ; without heparin , 1.14 percent ) . Older age , a higher Killip class , and the occurrence of anterior infa rct ion significantly increased the risk of stroke , whereas a higher body-mass index or a history of hypertension , diabetes , or smoking did not . CONCLUSIONS Patients with acute myocardial infa rct ion who receive thrombolytic therapy have a small risk of stroke . Treatment with t-PA as compared with streptokinase result ed in a small but significant excess of stroke . Subcutaneous heparin , given together with t-PA or streptokinase and aspirin , did not result in an increased risk of stroke The effects of dihydropyridine calcium antagonists on blood pressure and platelets , and the effects of aspirin on the circadian antihypertensive efficacy of dihydropyridines and on the 24-h platelet-activity profile , were the focus of a double-blind study . Patients with essential hypertension were treated for 8 weeks with either isradipine focus of double-blind study . Patients with essential hypertension were treated for 8 weeks with either isradipine ( 2.5 mg/day ) or nitrendipine ( 10 mg/day ) . Aspirin ( 100 mg/day ) was added to both treatment groups for a further 8 weeks . Measurements were taken after 4 weeks of placebo , after 8 weeks of dihydropyridine treatment , and after 8 weeks of treatment combined with aspirin .  Plasma levels of beta-thromboglobulin ( beta-TG ) and platelet aggregation induced by serotonin were measured six times during 24 h. Both dihydropyridines significantly lowered systolic and diastolic blood pressure . The addition of aspirin to dihydropyridine treatment had no significant effects on systolic or diastolic blood pressure .  Dihydropyridine treatment lowered the increased 24-h plasma beta-TG profile and inhibited platelet aggregability .  Aspirin added to nitrendipine led to a further significant decrease in beta-TG levels whereas its addition to isradipine was accompanied by a partial increase in plasma beta-TG . It is concluded that increases in platelet activity in hypertensive patients can be prevented with either isradipine alone or nitrendipine plus aspirin . Aspirin in a daily dose of 100 mg does not affect the antihypertensive efficacy of calcium antagonists BACKGROUND Nonsteroidal antiinflammatory drugs ( NSAIDs ) may alter blood pressure through their inhibitory effects on prostagl and in bio synthesis . Such potential hypertensive effects of NSAIDs have not been adequately examined in the elderly , who are the largest group of NSAID users . METHODS We performed a r and omized , double-blind , two-period crossover trial of ibuprofen ( 1800 mg per day ) vs placebo treatment in patients older than 60 years of age with hypertension controlled with hydrochlorothiazide .  While continuing their usual thiazide dosage , subjects were r and omized to a 4-week treatment period ( ibuprofen or placebo ) followed by a 2-week placebo wash-out period and a second 4-week treatment period with the alternative therapy .  Supine and st and ing systolic and diastolic blood pressures were measured weekly . RESULTS Of 25 r and omized subjects , 22 completed the study protocol ( mean age = 73 + /- 6.7 years ) .  Supine systolic blood pressure and st and ing systolic blood pressure were increased significantly with ibuprofen treatment , compared with placebo .  Mean supine systolic blood pressures were 143.8 + /- 21.0 and 139.6 + /- 15.9 mmHg on ibuprofen and placebo , respectively ( p = .004 ) . Mean st and ing systolic blood pressures were 148.1 + /- 19.9 and 143.4 + /- 17.9 mmHg on ibuprofen and placebo , respectively ( p = .002 ) . CONCLUSION We conclude that 1800 mg per day of ibuprofen does induce a significant increase in systolic blood pressure in older hypertensive patients treated with hydrochlorothiazide . NSAID therapy may negatively impact the control of hypertension in elderly patients The ability of angiotensin converting enzyme ( ACE ) inhibitors to lower blood pressure may in part be due to the formation of vasodilatory prostagl and ins . Inhibition of prostagl and in synthesis with aspirin may therefore theoretically attenuate the antihypertensive effect of ACE inhibitors . This trial studied the interaction between aspirin ( ASA ) and enalapril , an ACE inhibitor , and ASA and losartan , an angiotensin subtype 1 receptor antagonist .  Seventeen essential hypertensive patients were studied , maintained on a stable dose of either enalapril ( n = 7 ) or losartan ( n = 10 ) monotherapy for > or = 12 weeks before and throughout the study . Each patient received a 2-week course of placebo , 81 mg/day ASA , and 325 mg/day ASA , each treatment separated by a 2-week washout period . Blood pressure ( BP ) and serum thromboxane B2 ( TXB2 ) sample s were obtained at the end of each treatment period . Placebo was compared with each dose of ASA for each group . In both the enalapril and losartan groups , mean , systolic , and diastolic BP were unchanged with the addition of ASA .  Concentrations of TXB2 were suppressed to < 10 % in both groups with ASA . This study demonstrates that 81 to 325 mg/day ASA exerts no significant effect on BP in essential hypertensives taking enalapril or losartan BACKGROUND After angioplasty , major complications and ischemic events occur more frequently in diabetic than nondiabetic patients . To determine whether treatment with abciximab is effective in reducing these events in diabetics , we analyzed characteristics and outcomes of diabetic patients enrolled in a large multicenter study ( EPILOG ) . METHODS AND RESULTS Of 2792 patients enrolled , 638 ( 23 % ) were diabetic . Diabetic patients were older , shorter , and heavier ; more likely to be female and have three-vessel disease , prior coronary artery bypass graft surgery , a history of hypertension , or a recent myocardial infa rct ion ; and less likely to be current smokers than their nondiabetic counterparts . During hospitalization , death , myocardial infa rct ion , or urgent revascularization occurred in 7.1 % of diabetics and 7.5 % of nondiabetics . By 6 months , the composite of death and myocardial infa rct ion had occurred in 8.8 % of diabetic patients and 7.4 % of nondiabetics , whereas death , myocardial infa rct ion , or revascularization had occurred in 27.2 % and 22.6 % , respectively . Abciximab treatment reduced death or myocardial infa rct ion among diabetic and nondiabetic patients ( hazard ratios , 0.28 [ 95 % confidence interval ( CI ) , 0.13 to 0.57 ] and 0.47 [ 95 % CI , 0.33 to 0.70 ] at 30 days for diabetics and nondiabetics , respectively , and 0.36 [ 95 % CI , 0.21 to 0.61 ] and 0.60 [ 95 % CI , 0.44 to 0.82 ] at 6 months for diabetics and nondiabetics , respectively ) . Abciximab reduced target vessel revascularization among nondiabetic patients ( hazard ratio , 0.78 [ 95 % CI , 0.63 to 0.96 ] ) but not among diabetics ( hazard ratio , 1.4 [ 95 % CI , 0.94 to 2.08 ] ) . When st and ard- and low-dose heparin adjuncts were compared , diabetics receiving abciximab with st and ard-dose heparin had marginally greater reductions in the composite of death and myocardial infa rct ion and in target vessel revascularization than diabetics assigned to abciximab with low-dose heparin . CONCLUSIONS Abciximab treatment in diabetic patients led to a reduction in the composite of death and myocardial infa rct ion , which was at least as great as that seen in nondiabetic patients . However , target vessel revascularization was reduced in nondiabetic but not diabetic patients . This effect may be associated in part with lower doses of heparin . These differences may be related to differences in the platelet and coagulation systems between diabetics and nondiabetics , the greater extent of coronary artery disease in diabetics , or patient selection and management factors 240 patients were admitted to a double-blind study to determine the effect of long-term treatment with platelet-function inhibiting agents on occlusive arterial disease in the lower extremities . Patients were r and omised into 1 of 3 treatment groups : aspirin 330 mg ; dipyridamole 75 mg and aspirin 330 mg ; or matching placebo 3 times daily . The duration of treatment was 2 years . Arteriography was carried out at the beginning of the study and 2 years later or before if deterioration was observed . 199 patients completed the study according to the trial protocol . The serial arteriograms were assessed in pairs qualitatively , by means of simple comparative viewing , and semiquantitatively with Bollinger 's score system . Progression of the disease was most pronounced in the placebo-treated group , less so in the aspirin-treated group , and least of all in the dipyridamole- and -aspirin group . Patients who smoke and those with hypertension may benefit most from treatment with the 2 preparations under investigation A six year r and omised trial was conducted among 5139 apparently healthy male doctors to see whether 500 mg aspirin daily would reduce the incidence of and mortality from stroke , myocardial infa rct ion , or other vascular conditions . Though total mortality was 10 % lower in the treated than control group , this difference was not statistically significant and chiefly involved diseases other than stroke or myocardial infa rct ion . Likewise , there was no significant difference in the incidence of non-fatal myocardial infa rct ion or stroke — indeed , disabling strokes were somewhat commoner among those allocated aspirin . The lower confidence limit for the effect of aspirin on non-fatal stroke or myocardial infa rct ion , however , was a substantial 25 % reduction . Migraine and certain types of musculoskeletal pain were reported significantly less often in the treated than control group , but as the control group was not given a placebo the relevance of these findings was difficult to assess . There was no apparent reduction in the incidence of cataract in the treated group . The lack of any apparent reduction in disabling stroke or vascular death contrasts with the established value of antiplatelet treatment after occlusive vascular disease The associations of  diastolic blood pressure ( DBP )  with  stroke  and with coronary heart disease ( CHD ) were investigated in nine major prospect i ve observational studies : total 420,000 individuals , 843 strokes , and 4856 CHD events , 6 - 25 ( mean 10 ) years of follow-up . The combined results demonstrate positive , continuous , and apparently independent associations , with no significant heterogeneity of effect among different studies . Within the range of DBP studied ( about 70 - 110 mm Hg ) , there was no evidence of any " threshold " below which lower levels of DBP were not associated with lower risks of stroke and of CHD . Previous analyses have described the uncorrected associations of DBP measured just at " baseline " with subsequent disease rates . But , because of the diluting effects of r and om fluctuations in DBP , these substantially underestimate the true associations of the usual DBP ( ie , an individual 's long-term average DBP ) with disease . After correction for this " regression dilution " bias , prolonged differences in usual DBP of 5 , 7.5 , and 10 mm Hg were respectively associated with at least 34 % , 46 % , and 56 % less stroke and at least 21 % , 29 % , and 37 % less CHD . These associations are about 60 % greater than in previous uncorrected analyses . ( This regression dilution bias is quite general , so analogous corrections to the relations of cholesterol to CHD or of various other risk factors to CHD or to other diseases would likewise increase their estimated strengths . ) The DBP results suggest that for the large majority of individuals , whether conventionally " hypertensive " or " normotensive " , a lower blood pressure should eventually confer a lower risk of vascular disease BACKGROUND Clopidogrel is a new antiplatelet agent that offers increased protection over aspirin in preventing vascular ischaemic events in patients with symptomatic atherosclerosis . In a large , r and omized , international study of clopidogrel and aspirin ( n = 19,185 patients )  clopidogrel was associated with a lower incidence of gastrointestinal adverse events , including gastrointestinal haemorrhage and hospitalizations because of gastrointestinal haemorrhage . The aim of the study was to determine whether macroscopic differences in the gastric mucosa between  aspirin- and clopidogrel-treated subjects could be detected by gastroscopy after short-term treatment . METHODS Thirty-six healthy volunteers were r and omized in a double-blind , double-dummy , parallel design , to 75 mg/day of clopidogrel or 325 mg/day of aspirin for 8 days . Gastroscopy was performed at base line before administration of study drug and directly after treatment completion . Gastroduodenal effects were measured in accordance with a modified Lanza scale . RESULTS At base line no difference between the groups was detected ( median Lanza score , 0.0 in both groups ) . At the end of treatment the aspirin group showed a median score of 7.5 , and the clopidogrel group showed an unchanged median score of 0.0 ( P < 0.001 ) . In the aspirin group 13 individuals reported 19 adverse events versus 8 individuals and 13 adverse events for clopidogrel , with approximately half of the adverse events being gastrointestinal in each group . No serious adverse events were reported . CONCLUSION In contrast to aspirin , short-term treatment with clopidogrel does not induce macroscopic changes in the gastroduodenal mucosa . The study results show that in patients without gastroduodenal disease  clopidogrel , but not aspirin , does not induce any gastroscopically evident erosions during short-term treatment OBJECTIVE A secondary subgroup analysis of the European Stroke Prevention Study of the effect of antiplatelet medication on the risk of  myocardial infa rct ion . DESIGN AND SETTING A r and omized , double-blind placebo-controlled study with two parallel treatment groups ( dipyridamole plus aspirin and placebo ) . Sixteen centers from six countries participated in the study . PATIENTS A total of 2500 patients who had had one or more transient ischemic attacks or cerebral infa rct ions participated . INTERVENTION Combination therapy with dipyridamole ( 75 mg three times a day ) and aspirin ( 330 mg three times a day ) was compared with placebo during 24 months ' follow-up . OUTCOME MEASURES Prevention of fatal and nonfatal myocardial infa rct ion . RESULTS A total of 105 myocardial infa rct ions occurred in the intention-to-treat analysis and 76 occurred in the explanatory analysis . The overall risk reduction of myocardial infa rct ion with the study drugs was approximately 40 % in both statistical analyses , but the result was statistically significant only in the intention-to-treat analysis . Therapeutic efficacy was better among male patients , patients younger than 65 years , and patients with hypertension . CONCLUSION Combination therapy with dipyridamole and aspirin reduces not only the risk of cerebrovascular ischemic events but also the risk of myocardial infa rct ion Abstract Objective : To determine which groups of patients may derive particular benefit or experience harm from the use of low dose aspirin for the primary prevention of coronary heart disease . Design : R and omised controlled trial . Setting : 108 group practice s in the Medical Research Council 's general practice research framework who were taking part in the thrombosis prevention trial . Participants : 5499 men aged between 45 and 69 years at entry who were at increased risk of coronary heart disease . Main outcome measures : Myocardial infa rct ion , coronary death , and stroke . Results : Aspirin reduced coronary events by 20 % . This benefit , mainly for non-fatal events , was significantly greater the lower the systolic blood pressure at entry ( interaction P=0.0015 ) , the relative risk at pressures 130 mm Hg being 0.55 compared with 0.94 at pressures > 145 mm Hg . Aspirin also reduced strokes at low but not high pressures , the relative risks being 0.41 and 1.42 ( P=0.006 ) respectively . The relative risk of all major cardiovascular events — that is , the sum of coronary heart disease and stroke — was 0.59 at pressures < 130 mm Hg compared with 1.08 at pressures > 145 mm Hg ( P=0.0001 ) . Conclusion : Even with the limitations of subgroup analyses the evidence suggests that the benefit of low dose aspirin in primary prevention may occur mainly in those with lower systolic blood pressures , although it is not clear even in these men that the benefit outweighs the potential hazards . Men with higher pressures may be exposed to the risks of bleeding while deriving no benefit through reductions in coronary heart disease and stroke Nonsteroidal antiinflammatory drugs ( NSAIDs ) are known to attenuate the antihypertensive effects of a variety of antihypertensive agents including diuretics , beta-blockers , and vasodilators . Because of their unique mechanisms of actions , calcium channel blockers may not be subject to this interaction . This multicenter , double-blind , r and omized , placebo-controlled study was design ed to assess the effect of NSAID therapy on blood pressure control in stable hypertensive patients treated with a calcium channel blocker . One hundred patients with stable blood pressure control on 30 mg nicardipine three times a day were treated with 375 mg naproxen twice a day or placebo for 4 weeks . The mean diastolic blood pressures and estimated mean arterial pressures in both groups changed < 1 mm Hg during the 4 weeks of study drug treatment . None of the changes was significantly different from baseline and the two treatment groups were not significantly different from each other . Body weight in the placebo-treated patients did not change significantly whereas body weight in the naproxen-treated patients increased significantly , from 90.3 + /- 3.2 kg to 91.0 + /- 3.2 kg ( mean = 0.7 , P = .0003 ) . At 4 weeks there was a mean loss of 0.1 kg in the placebo group and a mean gain of 0.4 kg in the naproxen group compared to baseline weights , neither of which was statistically significant ( P = .60 and P = .071 , respectively ) . These results indicate that despite a significant increase in body weight , the antihypertensive action of the calcium channel blocker nicardipine is not significantly affected by cotreatment with naproxen Objective To test the hypothesis that an imbalance in intrarenal prostagl and ins plays a role in cyclosporin-induced nephrotoxicity . Methods and results Indomethacin was given in combination with cyclosporin to healthy volunteers .  Cyclosporin alone ( 10mg/kg twice a day ) for 4 days had no effect on effective renal plasma flow ( ERPF ) and glomerular filtration rate but 4 days of therapy with cyclosporin ( 10mg/kg twice a day ) and indomethacin ( 50 mg twice a day ) in combination result ed in a 37 % fall in glomerular filtration rate and a 32 % fall in ERPF . This suggests that autoregulatory mechanisms , possibly involving renal prostagl and ins , may participate in counteracting the tendency for cyclosporin-induced renal vasoconstriction in humans . Cyclosporin increased systemic blood pressure acutely , and this was not influenced by indomethacin even though indomethacin on its own caused sodium retention . This suggests that , in contrast to the renal vasculature , the systemic vascular response to cyclosporin is neither augmented nor buffered by prostagl and ins . Conclusion The reduction in intrarenal prostagl and ins clearly played a key role in the development of cyclosporin-induced renal vasoconstriction , but we could not demonstrate a role for prostagl and ins or for sodium retention in the initiation of cyclosporin-induced hypertension Sixteen hypertensive male out- patients ( 33 - 54 y ) , whose blood pressure ( BP ) had been normalized ( diastolic BP < 90 mmHg ) by treatment with a daily dose of 50 mg atenolol ( CAS 29122 - 68 - 7 ) , participated in this double-blind , placebo-controlled , parallel group study , which investigated the possible influence of the non-steroidal anti-inflammatory drug tenoxicam ( CAS 59804 - 37 - 4 ) on the control of BP by atenolol . After a run-in of 10 days , to assess the stability of BP control by atenolol , and to determine baseline parameters , 8 patients in group A received 20 mg tenoxicam ( 2 x 20 mg on days 1 and 2 ) , and 8 patients in group B received placebo , daily over 15 days ( days 0 - 14 ) , concomitantly with their atenolol regimen .  BP was measured under st and ardized conditions on several days . Heart rate ( EHR ) after 5 min of exercise by bicycle ergometry ( constant 75W ) , and parameters of renal function were assessed before ( baseline ) and during concomitant dosing of atenolol and tenoxicam . On day 14 the mean changes ( delta A , delta B ) from baseline of pre-dose BP ( mmHg ) and EHR ( beats/min ) in groups A and B , and the one-sided 95 % confidence regions ( R ) for delta A , respectively , were ( delta A , delta B , R ) : 4.4 , 1.6 , < 9.5 for sitting systolic BP , 2.8 , -0.3 , < 4.5 for sitting diastolic BP , -0.3 , -0.6 , < 5.5 for st and ing systolic BP , -0.6 , -1.9 , < 3.0 for st and ing diastolic BP , 0.4 , -7.5 , < 0.4 for EHR at pre-dose , 3.1 , 0.6 , < 7.8 for EHR at 3.5 h post-dose . ( ABSTRACT TRUNCATED AT 250 WORDS The effects of aspirin ( 1950 mg/day orally ) or indomethacin ( 75 mg/day orally ) on blood pressure were investigated in normotensive volunteers and hypertensive patients receiving antihypertensive medication .  Aspirin ( 1950 mg/day ) did not change blood pressure or body weight in normotensive or treated hypertensive subjects . No significant change in plasma renin concentration was seen with aspirin ( 1950 mg/day ) in treated hypertensive subjects . Indomethacin ( 75 mg/day ) significantly increased blood pressure in normotensive subjects and treated hypertensive subjects . Body weight increased significantly in the treated hypertensive subjects but not normotensive subjects . In treated hypertensive subjects indomethacin ( 75 mg/day ) did not change plasma volume , but significantly decreased plasma renin concentration This study tested the hypothesis that treatment with a nonsteroidal anti-inflammatory drug will not alter the hypotensive effect of a dihydropyridine calcium channel antagonist .  Fifteen essential hypertensives ( ages 58 - 80 years ) had a supine diastolic blood pressure ( DBP ) < 100 mmHg after 4 weeks monotherapy with nitrendipine 5 - 20 mg twice daily . They entered a double-blind r and omised crossover study in which the addition of indomethacin 25 mg three times daily was compared with placebo in treatment phases each of 4 weeks duration . Subjects were seen weekly and measurements in the last 2 weeks of each phase were compared . Supine blood pressure ( mean + /- SE ) was higher in the indomethacin phase ( 158 + /- 4/80 + /- 2 ) than in the placebo phase ( 154 + /- 4/76 + /- 3 ) ( p < 0.01 for DBP ) . In 6/15 ( 40 % ) of subjects the increase in supine diastolic blood pressure with indomethacin was > 5 mmHg . Plasma urea was also increased in the indomethacin phase : 7.6 + /- 0.6 mmol/l compared with placebo : 6.3 + /- 0.5 mmol/l ( p < 0.001 ) . The study has demonstrated that concurrent treatment with the NSAID indomethacin impairs the blood pressure lowering effect of the dihydropyridine calcium channel antagonist nitrendipine . This increase in blood pressure with indomethacin in subjects treated with nitrendipine may represent either an independent pressor effect of indomethacin or a reduced vasodilator prostanoid contribution to the hypotensive effect of nitrendipine . This blood pressure increase may be sufficient to interfere significantly with clinical blood pressure control in some subjects BACKGROUND Despite the use of antiplatelet agents , usually aspirin , in patients who have had an ischemic stroke , there is still a substantial rate of recurrence . Therefore , we investigated whether warfarin , which is effective and superior to aspirin in the prevention of cardiogenic embolism , would also prove superior in the prevention of recurrent ischemic stroke in patients with a prior noncardioembolic ischemic stroke . METHODS In a multicenter , double-blind , r and omized trial , we compared the effect of warfarin ( at a dose adjusted to produce an international normalized ratio of 1.4 to 2.8 ) and that of aspirin ( 325 mg per day ) on the combined primary end point of recurrent ischemic stroke or death from any cause within two years . RESULTS The two r and omized study groups were similar with respect to base-line risk factors . In the intention-to-treat analysis , no significant differences were found between the treatment groups in any of the outcomes measured . The primary end point of death or recurrent ischemic stroke was reached by 196 of 1103 patients assigned to warfarin ( 17.8 percent ) and 176 of 1103 assigned to aspirin ( 16.0 percent ; P=0.25 ; hazard ratio comparing warfarin with aspirin , 1.13 ; 95 percent confidence interval , 0.92 to 1.38 ) . The rates of major hemorrhage were low ( 2.22 per 100 patient-years in the warfarin group and 1.49 per 100 patient-years in the aspirin group ) . Also , there were no significant treatment-related differences in the frequency of or time to the primary end point or major hemorrhage according to the cause of the initial stroke ( 1237 patients had had previous small-vessel or lacunar infa rcts , 576 had had cryptogenic infa rcts , and 259 had had infa rcts design ated as due to severe stenosis or occlusion of a large artery ) . CONCLUSIONS Over two years , we found no difference between aspirin and warfarin in the prevention of recurrent ischemic stroke or death or in the rate of major hemorrhage . Consequently , we regard both warfarin and aspirin as reasonable therapeutic alternatives BACKGROUND The incidence of stroke in patients with acute coronary syndromes has not been clearly defined because few trials in this patient population have been large enough to provide stable estimates of stroke rates . METHODS AND RESULTS We studied the 10 948 patients with acute coronary syndromes without persistent ST-segment elevation who were r and omly assigned to placebo or the platelet glycoprotein IIb/IIIa receptor inhibitor eptifibatide in the Platelet Glycoprotein IIb/IIIa in Unstable Angina : Receptor Suppression Using Integrilin Therapy ( PURSUIT ) trial to determine stroke rates , stroke types , clinical outcomes in patients with stroke , and independent baseline clinical predictors for nonhemorrhagic stroke . Stroke occurred in 79 ( 0.7 % ) patients , with 66 ( 0.6 % ) nonhemorrhagic , 6 intracranial hemorrhages , 3 cerebral infa rct ions with hemorrhagic conversion , and 4 of uncertain cause . There were no differences in stroke rates between patients who received placebo and those assigned high-dose eptifibatide ( odds ratios and 95 % confidence intervals 0.82 [ 0.59 , 1.14 ] and 0.70 [ 0.49 , 0.99 ] , respectively ) . Of the 79 patients with stroke , 17 ( 22 % ) died within 30 days , and another 26 ( 32 % ) were disabled by hospital discharge or 30 days , whichever came first . Higher heart rate was the most important baseline clinical predictor of nonhemorrhagic stroke , followed by older age , prior anterior myocardial infa rct ion , prior stroke or transient ischemic attack , and diabetes mellitus . These factors were used to develop a simple scoring nomogram that can predict the risk of nonhemorrhagic stroke . CONCLUSIONS Stroke was an uncommon event in patients with acute coronary syndromes in the PURSUIT trial . These strokes are , however , associated with substantial morbidity and mortality rates . The majority of strokes were of nonhemorrhagic causes . Eptifibatide was not associated with an increase in intracranial hemorrhage , and no significant effect on nonhemorrhagic stroke was observed . We developed a useful nomogram for assigning baseline nonhemorrhagic stroke risk in this patient population The safety and pharmacodynamic compatibility of clopidogrel with medications commonly used in patients with atherosclerosis , such as , a beta-adrenergic receptor antagonist ( atenolol ) and a calcium uptake inhibitor ( nifedipine ) were assessed . Atenolol and nifedipine interactions with clopidogrel were studied in patients with peripheral arterial obstructive disease taking a well-established regimen of nifedipine ( N group of 6 patients ) and in patients with coronary artery disease taking a well-established regimen of either atenolol ( A group of 8 patients ) or of atenolol and nifedipine ( AN group of 8 patients ) . The study was conducted as a double-blind , r and omized , crossover comparison of clopidogrel , 75 mg once daily , and placebo treatment for 7 days , with a 14-day washout between treatments . Pharmacodynamic interactions between atenolol and nifedipine , either alone or in combination , and clopidogrel were assessed primarily on the clinical control of angina or hypertension and , secondarily , by comparing the extent of inhibition of ADP ( 5 microM)-induced platelet aggregation achieved between the 3 groups . The mean number of anginal episodes per patient during the placebo week was 1.50 , 9.0 and 11.5 in the A , N and AN groups , respectively ; during the week of clopidogrel treatment , it was 1.39 , 7.3 and 9.0 , respectively , indicating no change in occurrence . Likewise , review of the use of nitrates ( long or short acting ) did not suggest any major change in usage during any period of the study . ECGs did not change between the three recording times ( at screening and at the end of each treatment period ) . Vital signs were also unchanged throughout . Percent inhibition of platelet aggregation on day 7 was 31 % in the N group , 39 % in the A group , 28 % in the AN group , and 33 % overall . In conclusion , the coadministration of clopidogrel did not interfere with the clinical control of hypertension or angina established with atenolol or nifedipine , or both . Clopidogrel retained its full antiplatelet effect , and there were no safety problems caused by the coadministration Patients ( 303 ) who had had carotid territory transient ischemic attacks were r and omly assigned to aspirin or placebo treatments . Patients with amaurosis fugax  responded as well to aspirin as those with hemisphere events . Patients with lesions of the appropriate carotid artery  responded better to aspirin therapy than patients with no lesion or an occlusion . The  aspirin effect was the same across all risk-factor groups . Smoking had no effect on clinical outcome 1 . The haemodynamic effects of calcium antagonists could depend at least in part on the activity of vasoactive prostanoids . 2 . We set out to study the effect of the cyclo-oxygenase inhibitor ibuprofen , 400 mg three times daily for 3 days , by a r and omised cross-over study vs placebo in 12 mild to moderate essential hypertensive patients who had been treated for 1 month with amlodipine .  3 . Blood pressure , heart rate and vascular resistances in the upper limb ( Doppler ultrasound ) were measured . Plasma renin activity and urinary aldosterone , as well as indices of renal function , were evaluated . Urinary 2,3-dinor-6-keto-PGF1 alpha and 2,3-dinor-TXB2 , as well as 6-keto-PGF1 alpha and TXB2 , were measured as indices of systemic and renal PGI2 and TXA2 synthesis . 4 . Amlodipine normalised blood pressure and reduced upper limb vascular resistances ; it did not affect urinary prostanoid excretion . Short-term combined administration of ibuprofen result ed in , by comparison with placebo , inhibition of systemic PGI2 ( -80.5 ng 24 h-1 , 95 % CI -99.2 , -61.4 ; P < 0.001 ) and TXA2 ( -216.1 ng 24 h-1 , 95 % CI -276.5 , -155.8 ; P < 0.001 ) , together with an increase in systolic ( + 7.8 mm Hg , 95 % CI + 3.1 , + 12.3 ; P < 0.01 ) and diastolic ( + 3.9 mm Hg , 95 % CI + 1.2 , + 6.6 ; P < 0.01 ) blood pressure ; it had no significant effect on regional vascular resistances ( + 4.7 mm Hg ml-1 s , 95 % CI -5.6 , + 15.0 ) . Effects of ibuprofen on renal prostanoid synthesis were less marked , and there was no change in indices of renal function or hydro-electrolytic balance . ( ABSTRACT TRUNCATED AT 250 WORDS Objective Differences in renal synthesis between prostagl and ins I2 and E2 , and the relationships of the amounts synthesized to renin release were investigated in patients with essential hypertension . Methods Of 12 in patients , six had low to normal plasma renin activity and six had high renin activity . Before and 30 min after intravenous injection of aspirin D , L-lysine ( 18 mg/kg ) , abdominal aortic and renal venous plasma was sample d and assayed for renin activity , 6-keto-prostagl and in F1α ( as an index of prostagl and in I2 ) , and prostagl and in E2 . Results In patients with low to normal renin activity  , mean ± SD plasma levels of 6-keto-prostagl and in F1α were lower in the right and left renal veins ( 3.6 ± 1.4 and 4.1 ± 1.5 pg/ml , respectively ) than in the aorta ( 5.5 ± 2.0 pg/ml ) , but in the other patients , the levels in these veins ( 7.0 ± 2.4 and 6.5 ± 1.5 pg/ml ) were higher than in the aorta ( 5.4 ± 0.9 pg/ml ) . Plasma prostagl and in E2 levels in both veins were higher than in the aorta in both groups and , at each site , the levels were similar in the two groups . Aspirin suppressed renin release in the patients with high renin activity . Conclusions In patients with essential hypertension with low to normal renin activity , either less prostagl and in I2 than prostagl and in E2 is produced in the kidney or else more is metabolized there , and in such patients with high renin activity , the renal synthesis of prostagl and in I2 , more than that of prostagl and in E2 , seems to be related to the increased renin release BACKGROUND Repeat hospitalizations of patients with atherosclerosis represent a considerable burden on the health care system . We sought to determine whether clopidogrel compared with aspirin decreases the need for rehospitalization for ischemia and bleeding . METHODS AND RESULTS The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events ( CAPRIE ) trial was a r and omized , blinded , multicenter , trial of 19,185 patients with atherosclerotic disease manifested as recent ischemic stroke or myocardial infa rct ion or symptomatic peripheral arterial disease . Without any double-counting of events , the number of rehospitalizations for ischemic events ( defined as angina , transient ischemic attack , or limb ischemia ) or bleeding events was determined for the entire cohort . There was a significant reduction in the total number of rehospitalizations for ischemic events or bleeding with clopidogrel use compared with aspirin ( 1502 vs 1673 ; P = .010 ) over an average of 1.6 years of treatment . This reduction in rehospitalization was consistent across individual outcomes of angina , transient ischemic attack , limb ischemia , and bleeding . Compared with aspirin , clopidogrel also result ed in a 7.9 % relative risk reduction in a combined end point of vascular death , stroke , myocardial infa rct ion , or rehospitalization for ischemic events or bleeding ( 15.1 % to 13.7 % at 1 year ; P = .011 ) . Adjusting for baseline prognostic variables , clopidogrel therapy was an independent predictor for reduction of vascular death , stroke , myocardial infa rct ion , or rehospitalization for ischemic events or bleeding ( P = .009 ) . CONCLUSIONS Treatment with clopidogrel results in a significant decrease in the need for rehospitalization for ischemic events or bleeding compared with aspirin . This meaningful end point tracks well with other , more traditional measures of outcome and has incremental value beyond such end points Some of the antihypertensive effects of angiotensin-converting enzyme ( ACE ) inhibitors occur through nonangiotensin II-mediated mechanisms . One of these is through decreased kinin degradation , leading to enhanced production of vasodilator arachidonic acid metabolites . It was reasoned that if ACE inhibition also leads to an increase in the production of the potent vasoconstrictor thromboxane A2 , then maneuvers that selectively inhibit thromboxane production without reducing prostagl and ins ( PG ) E2 + PGI2 might enhance the antihypertensive effect of ACE inhibition . This double-blinded , r and omized , crossover study was therefore undertaken to determine : ( 1 ) if captopril increases platelet and /or renal thromboxane production ; and ( 2 ) if low-dose aspirin enhances the antihypertensive effect of captopril .  Patients with mild essential hypertension and no other significant medical problems were studied . In a double-blinded , r and om order , patients took captopril alone ( 25 mg every 12 h ) for 2 wk and captopril plus aspirin ( 75 mg/day ) for another 2 wk . Active treatment periods were preceded by 2 wk of single-blind placebo .  Fifteen patients with a mean age of 53 yr and an average mean arterial pressure ( MAP ) of 114 + /- 8 ( + /- SD ) mm Hg were studied .  Serum thromboxane B2 was higher ( P < 0.05 ) during treatment with captopril/placebo ( 600 + /- 46 ( + /- SE ) pg/mL ) than during the two washout periods combined ( 420 + /- 57 and 553 + /- 78 ) and was lowest ( P < 0.0005 ) during treatment with captopril/aspirin ( 302 + /- 36 ) . Captopril treatment significantly increased the urinary excretion of PGE2 ( P = 0.038 ) . Captopril/placebo significantly lowered MAP ( P < 0.05 ) to 105.0 + /- 3.7 mm Hg compared with the washout period . However , the addition of aspirin to captopril caused no additional lowering of MAP ( 105.2 + /- 2.8 mm Hg ) . It was concluded that treatment with captopril does increase platelet thromboxane production . However , lowering platelet thromboxane with low doses of aspirin may not enhance the antihypertensive effect of captopril The effects of non-steroidal anti-inflammatory drugs ( NSAIDs ) on the blood pressure and renal function of essential hypertensive patients depend on the specific type of NSAID and antihypertensive drug administered . Twelve patients with essential hypertension , aged 35 to 59 years , stabilized ( blood pressure less than 140/90 mmHg ) with captopril  , received ketoprofen ( 100 mg bid for 7 days ) or matching placebo in a r and omized double-blind cross-over fashion . A 3-week wash-out period was included between treatment periods . Blood pressure on the first and last days of the placebo treatment period ( 137 + /- 7 (SD)/80 + /- 8 and 139 + /- 11/81 + /- 9 mmHg ) was similar to respective values during ketoprofen therapy ( 136 + /- 10/79 + /- 7 and 143 + /- 10/81 + /- 9 mmHg ) . The mean differences in systolic and diastolic blood pressures , at the end of the treatment periods , between ketoprofen and placebo were 4 ( 95 % confidence intervals -5 , + 13 ) and 0 (-8 , + 8) mmHg , respectively . Ketoprofen had no effect on 24-h urinary sodium excretion ( 160 + /- 33 and 147 + /- 39 mmol/24 h for ketoprofen and placebo , respectively ) . Ketoprofen was without effect on glomerular filtration rate , renal plasma flow and filtration fraction . In conclusion , our data suggest that ketoprofen is a safe choice when short-term treatment with a NSAID is indicated in an essential hypertensive patient treated with a converting enzyme inhibitor such as captopril A double-blind study was established to evaluate the platelet aggregation inhibiting effect of ticlopidine on the course of ocular vein occlusions . 35 patients with recent central retinal vein occlusions and 54 patients with retinal branch vein occlusions were treated for 6 months . Various ophthalmological and clinical -chemical parameters , including fluorescence angiography , were assessed . Compared with placebo therapy a significant improvement in visual acuity was observed with ticlopidine for branch vein occlusions ; the same trend was seen for the central retinal vein occlusions . Increased ADP-induced platelet aggregation was frequently found : in 72 % of the central retinal vein occlusions and 70 % of the branch vein occlusions . For the Wu and Hoak test , these numbers were respectively 74 % and 67 % . Hypertension was seen in 55 % of all occlusions , hyperlipaemia in 33 % , and diabetes in 29 % . The effect of ticlopidine was most pronounced in patients with increased platelet aggregation and least obvious in hyperlipaemia . Hypertension and diabetes did not apparently influence Ticlopidine 's effects . It is concluded that the platelet aggregation inhibitor ticlopidine is effective in the treatment of recent ocular vein occlusions The use of cyclooxygenase inhibitors has been seen to reduce the efficacy of many antihypertensive drugs . However , cyclooxygenase inhibitors are normally non-selective because they affect both vascular tissue , where the endothelial prostanoids exert principally a vasodilatory action , and the kidneys , where they also play an important role in regulating hydroelectrolytic metabolism by redistribution of intraparenchymal flow . To evaluate the relative importance of vascular district in the hypertensive patient , we administered ibuprofen - a drug acting with only a minimal antagonist activity . A group of 20 male hypertensives were r and omly allocated , according to a single-blind protocol , to treatment with amlodipine ( A , 10 mg/day ) or lisinopril ( L , 20 mg/day ) . Blood pressure was significantly reduced after 30 days , with a mean difference of -21.75 mmHg for systolic blood pressure ( SBP ) ( 95 % confidence interval ( Cl ) : -27.46 to -16.04 ; P < 0.0001 ) and -14.15 mmHg for diastolic blood pressure ( DBP ) ( 95 % Cl : -17.13 to -11.17 ; P < 0.0001 ) . Brachial artery compliance showed a mean increase of 1.657 x 10(-7 ) dyn-1 cm(4 ) ( 95 % Cl : 1.188 to 2.126 ; P<0.001 ) , and forearm resistances showed a mean decrease of -41.973 mmHg ml(-1)s ( 95 % Cl : -75.479 to -8.467 ; P = 0.017 ) . Changes in compliance were significantly related to those in SBP ( r= -0.546 ; P= 0.013 ) . The administration of ibuprofen ( 400 mg , three times a day for 3 days ) was accompanied by a slight but significant increase in SBP , but not in brachial artery compliance or forearm resistances . Only SBP was affected , showing a mean increase of 4.25 mmHg ( 95 % Cl : 1.26 to 7.24 ; P = 0.008 ) . There was also reduced urinary excretion of PGI(2 ) and TXA(2 ) metabolites . The mean change in 6-keto-PGF(1 alpha ) and 2,3-dinor-6-keto-PGF(1 alpha ) was 45.71 ng per g urinary creatinine ( uCr ) ( 95 % Cl : -0.16 to-91.25 ; P= 0.049 ) and -73.17 ng ( g uCr)(-1 ) ( 95 % Cl : -38.81 to -107.53 ; P<0.001 ) , respectively . The mean decrease in TXA(2 ) catabolites was highly significant : -39.2 ng ( g uCr)(-1 ) ( 95 % Cl : -18.17 to-60.22 ; P < 0.001 ) and -102.87 ng ( g uCr)(-1 ) ( 95 % Cl : -61.86 to -143.88 ; P < 0.001 ) for TXB(2 ) and 2,3-dinor-TXB(2 ) , respectively . Our study highlighted an inverse correlation between changes in blood pressure and those in urinary 2,3-dinor-6-keto-PGF(1alpha ) excretion , irrespective of antihypertensive regimen . This suggests that , in the hypertensive patient treated with NSAIDs , inhibition of vascular prostanoid synthesis may play an important role in countering the efficacy of an important vascular tone regulatory mechanism Aspirin at low doses is used as an inhibitor of platelet aggregation and is frequently administered to essential hypertensive patients with arterial thrombotic complications . However , it is unknown whether aspirin can modify blood pressure values either in treated or untreated hypertensive patients , as described for other non steroidal anti-inflammatory drugs . Thus 30 patients . 10 with mild uncomplicated and untreated essential hypertension , 10 with essential hypertension under chronic treatment with captopril , 50 mg bid , and 10 with essential hypertension under chronic treatment with atenolol , 100 mg oid , received aspirin , 100 mg oid , and the corresponding placebo for one month , according to a double blind r and omized cross-over design . At the end of each treatment , blood pressure , heart rate , generated serum thromboxane B2 and urinary excretion of thromboxane B2 and 6 keto prostagl and in F1 alpha and plasma renin activity were measured . Both in treated and untreated essential hypertensive patients , aspirin administration did not affect blood pressure , heart rate and urinary 6 keto prostagl and in F1 alpha , while it significantly reduced serum and urinary excretion of thromboxane B2 and plasma renin activity . In conclusion , while the present data confirm that low doses of aspirin selectively inhibit thromboxane B2 synthesis , they indicate that aspirin at 100 mg oid can be administered to treated and untreated essential hypertensive patients without any harmful effect on blood pressure values Background Arthritis and hypertension are common comorbid conditions affecting elderly adults . Use of nonsteroidal anti-inflammatory drugs in patients treated with antihypertensive medication can lead to destabilization of blood pressure control and other cardiorenal events . The potential for similar interactions with cyclooxygenase-2–specific inhibitors has not been fully explored . The authors evaluated the cardiorenal safety of two new cyclooxygenase-2–specific inhibitors , celecoxib and rofecoxib . Methods This study was a 6-week , r and omized , parallel-group , double-blind trial in patients with osteoarthritis who were ≥65 years of age and were taking antihypertensive agents . Patients received once-daily celecoxib 200 mg or rofecoxib 25 mg . The primary endpoints were the development of edema , changes in systolic blood pressure , and changes in diastolic blood pressure as measured at any time point in the study . Measurements occurred at baseline and after 1 , 2 , and 6 weeks of treatment . Findings Eight hundred ten patients received study medication  ( celecoxib , n = 411 ; rofecoxib , n = 399 ) . Nearly twice as many rofecoxib-compared with celecoxib-treated patients experienced edema ( 9.5 % vs. 4.9 % , P = 0.014 ) . Systolic blood pressure increased significantly in 17 % of rofecoxib-compared with 11 % of celecoxib-treated patients ( P = 0.032 ) at any study time point . Diastolic blood pressure increased in 2.3 % of rofecoxib-compared with 1.5 % of celecoxib-treated patients ( P = 0.44 ) . At week 6 , the change from baseline in mean systolic blood pressure was + 2.6 mmHg for rofecoxib compared with −0.5 mmHg for celecoxib ( P = 0.007 ) . Conclusions Patients taking antihypertensive therapy and receiving cyclooxygenase-2–specific inhibitors should be monitored for the development of cardiorenal events . Patients receiving celecoxib experienced less edema and less destabilization of blood pressure control compared with those receiving rofecoxib There are conflicting reports on the interaction of aspirin with angiotensin-converting enzyme inhibitors in heart failure and systemic hypertension . A post hoc analysis of the Captopril and Thrombolysis Study ( CATS ) study was conducted . At r and omization , 94 patients ( 31.5 % ) took aspirin .  In patients who took aspirin , the cumulative alpha-hydroxy butyrate dehydrogenase release was 1,151 + /- 132 IU/L in patients r and omized to captopril compared with 1,401 + /- 136 IU/L in patients r and omized to placebo ( difference -250 + /- 189 [ 95 % confidence interval ( CI ) -620 to 120 ] ) . This difference was comparable to the difference in patients who did not use aspirin ( -199 + /- 147 [ 95 % CI -488 to 897 ] ) . One year after acute myocardial infa rct ion , an increase in left ventricular end-diastolic volume index of 2.2 + /- 3.0 ml/m2 in captopril-treated and 1.9 + /- 2.9 ml/m2 in placebo-treated patients was observed in patients who took aspirin ( difference 0.4 + /- 4.2 [ 95 % CI -8.2 to 8.9 ] ) . This difference was also comparable to the difference in patients who did not take aspirin ( 2.2 + /- 3.8 [ 95 % CI -5.2 to 9.7 ] ) . One year after acute myocardial infa rct ion , patients who did take aspirin had a mean change in LV end-diastolic volume index of 2.1 + /- 2.1 ml/m2 compared with 8.4 + /- 1.9 ml/m2 in patients who did not use aspirin ( p = 0.02 ) . Thus , aspirin does not attenuate the acute and long-term effects of angiotensin-converting enzyme inhibition after acute myocardial infa rct ion , but independently reduces LV dilation after myocardial infa rct ion Thirty-seven patients affected by polycythaemia rubra vera ( PRV ) and with at least one additional thrombotic risk factor ( overt vascular disease , diabetes mellitus , treated hypertension , smoking habit , plasma hyperviscosity , hyperfibrinogenemia ) were enrolled in a double-blind r and omized placebo-controlled study , and 18 were given ticlopidine 250 mg , b.i.d . , for 60 days . All the patients had previously been su bmi tted to cytoreduction , and PRV was under control in all cases at the start of the study . During the study , the haematological parameters were controlled every 15 days , and venesection was performed if haematocrit was greater than 46 % . Whole blood viscosity , at low and high shear rates , plasma viscosity , and fibrinogen were measured on days 0 and 60 . In the ticlopidine group , we recorded a significant 13.14 % reduction of the mean fibrinogen level after treatment ( 390 + /- 63 vs. 449 + /- 97 mg/dl , p less than 0.01 ) . All the other haemorheological parameters were not significantly modified by ticlopidine treatment , nor were there significant modifications recorded in the placebo group . Our study shows that ticlopidine may reduce a probable thrombotic risk factor ( hyperfibrinogenemia ) in PRV patients A comparative study of the prevention of recurrences of  cerebral transient ischemic attacks  during a 6-month observation period was conducted in 73 patients treated with a combination of acetylsalicylic acid and dipyridamole ( ASAD , 1,050 mg + 150 mg/day ) and in 65 patients treated with pentoxifylline ( PTX 1,200 mg/day , Trental 400 t.d.s . ) . The patients were r and omly assigned to the treatments . Risk factor analysis showed high prevalence of arterial hypertension , hyperlipidemia and smoking in these patients . The two groups were matched in terms of age , sex , blood pressure and site of TIA origin ( carotid 63 % in the ASAD , 65 % in the PTX group ) . 23 ASAD patients and 9 PTX patients suffered a recurrence . There were 4 nonfatal stroke events with ASAD and 2 with PTX . 80 recurrent TIAs were recorded in 19 ASAD patients compared with 19 such episodes in 9 PTX subjects . The morbidity rates ( life table analysis ) were significantly lower ( p less than 0.05 ) in the PTX group . The results of the study point to a preventive effect of PTX in terms of the reduction in TIA recurrences
target: Acetylsalicylic acid ( ASA ) did not reduce stroke or ' all cardiovascular events ' compared to placebo in primary prevention patients with elevated blood pressure and no prior cardiovascular disease .
  Antiplatelet therapy with ASA for primary prevention in patients with elevated blood pressure provides a benefit , reduction in myocardial infa rct ion , which is negated by a harm of similar magnitude , increase in major haemorrhage .
  The benefit of antiplatelet therapy for secondary prevention in patients with elevated blood pressure is many times greater than the harm .
  Benefit has not been demonstrated for warfarin therapy alone or in combination with aspirin in patients with elevated blood pressure .
background: BACKGROUND Elevated systemic blood pressure results in high intravascular pressure but the main complications , coronary heart disease ( CHD ) , ischaemic strokes and peripheral vascular disease ( PVD ) , are related to thrombosis rather than haemorrhage .
  Some complications related to elevated blood pressure , heart failure or atrial fibrillation , are themselves associated with stroke and thromboembolism .
  Therefore it is important to investigate if antithrombotic therapy may be useful in preventing thrombosis-related complications in patients with elevated blood pressure .
  OBJECTIVES To conduct a systematic review of the role of antiplatelet therapy and anticoagulation in patients with high blood pressure , including those with elevations in both systolic and diastolic blood pressure , isolated elevations of either systolic or diastolic blood pressure , to address the following hypotheses : ( i ) antiplatelet agents reduce total deaths and /or major thrombotic events when compared to placebo or other active treatment ; and ( ii ) oral anticoagulants reduce total deaths and /or major thromboembolic events when compared to placebo or other active treatment .
  Ticlopidine , clopidogrel and newer antiplatelet agents such as prasugrel and ticagrelor have not been sufficiently evaluated in patients with high blood pressure .