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Haemorrhagic and thromboembolic complications in patients with atrial fibrillation on anticoagulant prophylaxis.

We studied clinically relevant haemorrhagic and thromboembolic events in 213 patients with atrial fibrillation (AF) during 818 patient-years of anticoagulant (AC) treatment. The incidence of complicating events per 100 patient-years of treatment in three groups of patients, those with mitral valve disease (MVD; n = 34), without MVD (n = 102) and those with previous thromboembolism (TE; n = 77) was: major peripheral haemorrhages 3.1, 3.3 and 8.2 (non-MVD vs. TE group, P less than 0.05), cerebrovascular events 3.9, 3.0 and 3.0 (NS), and peripheral arterial thromboembolism 0, 0 and 1.5 (non-MVD vs. TE group, P less than 0.05). The proportion of thrombotest values less than 5 and/or greater than 20% at regular check-ups was 9.8% in patients with and 6.9% in patients without major peripheral haemorrhages (P less than 0.01). Major peripheral haemorrhages are frequent in patients with AF receiving AC treatment. They are most likely to occur in those with previous thromboembolism and among those with unstable AC control.

Aged↗

Antenatal use of enoxaparin for prevention and treatment of thromboembolism in pregnancy.

OBJECTIVE: To assess the safety and efficacy of enoxaparin use for thromboprophylaxis or treatment of venous thromboembolism during pregnancy. DESIGN: Retrospective review of casenotes of women who received enoxaparin during pregnancy. SETTING: Obstetric Medicine Unit at Glasgow Royal Maternity Hospital. SAMPLE: Data were obtained on 57 pregnancies in 50 women over six years. METHODS: Information was obtained from case records in relation to outcome measures, the presence of underlying thrombophilia and indication for anticoagulation. MAIN OUTCOME MEASURES: Incidences of venous thromboembolism, haemorrhage, thrombocytopenia, peak plasma anti-factor Xa levels and symptomatic osteoporosis. RESULTS: There were no thromboembolic events in the thromboprophylaxis group. There were no incidences of heparin-induced thrombocytopenia. Twenty-two women had spinal or epidural anaesthesia and no complications were encountered. There was one instance of antepartum haemorrhage following attempted amniotomy in a woman with previously unknown vasa praevia. Two women sustained postpartum haemorrhage, both secondary to vaginal lacerations, resulting in blood loss > 1,000 mL. Blood loss following caesarean section was not excessive. No instances of vertebral or hip fracture were encountered. The median peak plasma anti-factor Xa level on a dose of 40 mg once daily was 0.235 U/mL; peak plasma anti-factor Xa levels were not affected by gestational age. CONCLUSIONS: The use of enoxaparin in pregnancy is associated with a low incidence of complications and a dose of 40 mg once daily throughout pregnancy provides satisfactory anti-factor Xa levels and appears effective in preventing venous thromboembolism.

Adolescent↗

Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series.

OBJECTIVES: To assess the use of low molecular weight heparin for the treatment of venous thromboembolism in pregnancy. DESIGN: A prospective observational study. SETTING: The maternity units in two university teaching hospitals and one district general teaching hospital. POPULATION: Thirty-six consecutive women presenting with objectively diagnosed venous thromboembolism during pregnancy and the immediate puerperium. METHODS: Treatment with the low molecular weight heparin enoxaparin, approximately 1 mg/kg s.c., twice daily, based on early pregnancy weight. MAIN OUTCOME MEASURES: Peak anti-Xa activity (three hours post-injection), alterations in treatment, side effects and the use of regional anaesthesia. RESULTS: In 33 women, the initial dose of enoxaparin provided satisfactory peak anti-Xa activity (median 0.8 u/mL, range 0.44-1.0 u/mL) and was continued. Three women required dose reduction since peak anti-Xa activities were above the therapeutic range (1.2, 1.2 and 1.1 u/mL). No woman developed thrombocytopaenia, haemorrhagic complication or further thromboembolic episode. Two women developed allergic skin reactions on enoxaparin and were changed to tinzaparin. Fifteen women had regional anaesthesia for delivery, with a reduced dose of enoxaparin (40 mg once daily), all without complication. CONCLUSIONS: Enoxaparin is a safe and effective treatment for venous thromboembolism during pregnancy and confers a major advantage over unfractionated heparin through its simplified regimen of administration.

Adult↗

Efficacy of ticlopidine in the prevention of thromboembolic events in patients with VVI pacemakers.

This study was designed to evaluate whether long-term treatment with ticlopidine reduces the incidence of thromboembolic episodes in patients with a VVI pacemaker. One hundred eleven patients with a VVI pacemaker were randomly assigned to two groups: group A (52 patients) was treated with ticlopidine at the dose of 250 mg a day; and group B (59 patients) was not treated and served as a control group. The primary analysis of efficacy of ticlopidine was based on the occurrence of thromboembolic episodes and of cardiovascular and cerebrovascular deaths. The mean follow-up period was 66 months. In group A, there was a significant reduction in the incidence of thromboembolic episodes (P less than 0.05) with a smaller incidence of total cardiovascular and cerebrovascular deaths (8 in group A and 18 in group B; P = 0.05) as compared with group B. Twelve percent of patients had moderate side effects with 1 dropout (epistaxis). Our data confirm the high incidence of thromboembolic events in patients with a VVI pacemaker and demonstrate the efficacy of ticlopidine in preventing them.

Aged↗

Risk of thromboembolism in acute atrial fibrillation or atrial flutter.

Atrial fibrillation (AF) is the most common sustained cardiac dysrhythmia, predominating in the elderly, with stroke as a potentially devastating complication. Prevention of the thromboembolic sequelae from AF remains a central focus of practicing clinicians. Although the risk of thromboembolism in chronic AF is well recognized, less is known about the potential risk of systemic embolism in acute AF. In addition, recent data support the notion of a group at considerable risk of embolism from atrial flutter, an arrhythmia typically believed to bestow little increased risk of thromboembolism. The mechanism of thrombus formation, embolization, and resolution in atrial arrhythmias is not well defined, particularly in that of acute AF or atrial flutter. The traditional concept proposes that atrial thrombus forms only after > 2 days of AF and embolizes by being dislodged from increases in shear forces. This widely accepted concept further holds that newly formed atrial thrombus, in the setting of AF, organizes over a span of 14 days. The results of studies based on observations from transesophageal echocardiography examinations have provided provocative insight into the temporal sequence of atrial thrombus formation, embolization, and resolution in AF or atrial flutter and have expanded the traditional concept of thromboembolism in these atrial dysrhythmias. Namely, left atrial thrombus may form before the onset of AF in the face of sinus rhythm. Conversion to sinus rhythm may increase the thrombogenic milieu of the left atrium. Importantly, atrial thrombus may form in the acute phase of AF. Last, thrombi may require > 14 days to become immobile or to resolve. Findings similar to those of acute AF have been reported in patients with atrial flutter and coexisting cardiac pathology. On the basis of these emerging insights fostered by the use of transesophageal echocardiography, it appears appropriate to consider anticoagulation in patients presenting with acute AF or atrial flutter with coexisting cardiac pathology predisposing to left atrial thrombus.

Acute Disease↗

Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs.

Reports of thromboembolism following the use of oral contraceptives received by drug safety committees in the United Kingdom, Sweden, and Denmark have been analysed to investigate possible differences in the risks associated with the various preparations. For this purpose the numbers of reports of thromboembolism attributed to each product were compared with the distribution that would have been expected from market research estimates of sales, assuming that all products carried the same risk.A positive correlation was found between the dose of oestrogen and the risk of pulmonary embolism, deep vein thrombosis, cerebral thrombosis, and coronary thrombosis in the United Kingdom. A similar association was found for venous thrombosis and pulmonary embolism in Sweden and Denmark. No significant differences could be detected between sequential and combined preparations containing the same doses of oestrogen, nor between the two oestrogens, ethinyloestradiol and mestranol.Certain discrepancies in the data suggest that the dose of oestrogen may not be the only factor related to the risk of thromboembolism; thus there was a significant deficit of reports associated with the combination of mestranol 100 mug. with norethynodrel 2.5 mg. and a significant excess of reports associated with the combination of ethinyloestradiol 50 mug. with megestrol acetate 4 mg. An excess of reports also occurred with other combined preparations containing megestrol acetate.The data obtained in earlier epidemiological studies were re-examined and, though no trend was obvious in any one of them, the combined results showed an excess of cases of thromboembolism at the highest dose of oestrogen.The finding of a positive correlation between the dose of oestrogen and the risk of coronary thrombosis is of special interest since previous studies have failed to provide clear evidence of a relationship between oral contraceptives and this condition.

Contraceptives, Oral↗

Postoperative thromboembolism and the use of oral contraceptives.

We have previously reported the results of a retrospective study of the relationship between oral contraceptives and deep vein thrombosis and pulmonary embolism occurring in the absence of an evident predisposing cause. The present paper describes a similar investigation of the relationship between oral contraceptives and thromboembolism following certain surgical procedures.Of 30 patients with thromboembolism, 12 (40%) had been using oral contraceptives during the month preceding surgery, while only 9 of 60 matched controls (15%) had been doing so. From these data it is estimated that the risk of postoperative thromboembolism is increased threefold to fourfold by the use of contraceptive steroids.It is recognized that few of the episodes of deep vein thrombosis and pulmonary embolism that occur postoperatively are detectable clinically, and that not all of these are recorded in discharge summaries or diagnostic indexes. Despite these considerations, we have been unable to detect any important bias in the data which could account for the observed association between oral contraceptives and the development of postoperative thromboembolism.

Adolescent↗

Effect of 1995 pill scare on rates of venous thromboembolism among women taking combined oral contraceptives: analysis of general practice research database.

OBJECTIVE: To compare the incidence of venous thromboembolism among women taking combined oral contraceptives before and after the October 1995 pill scare. DESIGN: Analysis of General Practice Research Database. SETTING: United Kingdom, January 1993 to December 1998. SUBJECTS: Women aged 15-49 taking combined oral contraceptives. MAIN OUTCOME MEASURES: Incidence of venous thromboembolism. RESULTS: Use of so called "third generation" combined oral contraceptives fell from 53% during January 1993 to October 1995 to 14% during November 1995 to December 1998. There was no significant change in the incidence of venous thromboembolism between the two periods after age was adjusted for (incidence ratio 1.04, 95% confidence interval 0.78 to 1.39). CONCLUSIONS: The findings are not compatible with the assertion that third generation oral contraceptives are associated with a twofold increase in risk of venous thromboembolism compared with older progestogens.

Adolescent↗

Atrial fibrillation: relation between clinical risk factors and transoesophageal echocardiographic risk factors for thromboembolism.

OBJECTIVE: To correlate clinical risk factors for thromboembolism with transoesophageal echocardiography (TOE) markers of a thrombogenic milieu. DESIGN: Clinical risk factors for thromboembolism and TOE markers of a thrombogenic milieu were assessed in consecutive patients with non-rheumatic atrial fibrillation. The following TOE parameters were assessed: presence of spontaneous echo contrast, thrombi, and left atrial appendage blood flow velocities. A history of hypertension, diabetes mellitus, or thromboembolic events, patient age > 65 years, and chronic heart failure were considered to be clinical risk factors for thromboembolism. SETTING: Tertiary cardiac care centre. PATIENTS: 301 consecutive patients with non-rheumatic atrial fibrillation scheduled for TOE. RESULTS: 255 patients presented with clinical risk factors. 158 patients had reduced left atrial blood flow velocities, dense spontaneous echo contrast, or both. Logistic regression analysis showed that a reduced left ventricular ejection fraction and age > 65 years were the only independent predictors of a thrombogenic milieu (both p < 0.0001). The probability of having a thrombogenic milieu increased with the number of clinical risk factors present (p < 0.0001). 17.4% of the patients without clinical risk factors had a thrombogenic milieu whereas 41.2% of the patients presenting one or more clinical risk factors had none. CONCLUSION: There is a close relation between clinical risk factors and TOE markers of a thrombogenic milieu. In addition, TOE examination allows for the identification of patients with a thrombogenic milieu without clinical risk factors.

Aged↗

Incidence of atrial fibrillation and thromboembolism in a randomised trial of atrial versus dual chamber pacing in 177 patients with sick sinus syndrome.

OBJECTIVE: To analyse the occurrence of atrial fibrillation (AF) and thromboembolism in a randomised comparison of rate adaptive single chamber atrial pacing (AAIR) and dual chamber pacing (DDDR) in patients with sick sinus syndrome and normal atrioventricular (AV) conduction, in which left atrial dilatation and decreased left ventricular fractional shortening had been observed in the DDDR group. METHODS: 177 consecutive patients with sick sinus syndrome (mean (SD) age 74 (9) years, 104 women) were randomly assigned to treatment with one of three pacemakers: AAIR (n = 54), DDDR with a short rate adaptive AV delay (n = 60) (DDDR-s); or DDDR with a fixed long AV delay (n = 63) (DDDR-l). Analysis was intention to treat. RESULTS: Mean follow up was 2.9 (1.1) years. AF at one or more ambulatory visits was significantly less common in the AAIR group (4 (7.4%) v 14 (23.3%) in the DDDR-s group v 11 (17.5%) in the DDDR-l group; p = 0.03, log rank test). The risk of developing AF in the AAIR group compared with the DDDR-s group was significantly decreased after adjustment for brady-tachy syndrome in a Cox regression analysis (relative risk 0.27, 95% confidence interval (CI) 0.09 to 0.83, p = 0.02). The benefit of AAIR was highest among patients with brady-tachy syndrome. Brady-tachy syndrome and a thromboembolic event before pacemaker implantation were independent predictors of thromboembolism during follow up (relative risk 7.5, 95% CI 1.6 to 36.2, p = 0.01, and relative risk 4.7, 95% CI 1.2 to 17.9, p = 0.02, respectively). CONCLUSIONS: During a mean follow up of 2.9 years AAIR was associated with significantly less AF. The beneficial effect of AAIR was still significant after adjustment for brady-tachy syndrome. Brady-tachy syndrome was associated with an increased risk of thromboembolism.

Adult↗

Thromboembolism after atrioventricular node ablation and pacing: long term follow up.

OBJECTIVE: To assess the incidence of arterial embolic events in patients with high rate, drug resistant, severely symptomatic paroxysmal and chronic atrial fibrillation who have undergone atrioventricular (AV) node ablation and permanent pacing. DESIGN: Multicentre retrospective cohort study. PATIENTS AND MANAGEMENT: From May 1987 to January 1997, AV node ablation was performed in 585 severely symptomatic patients (mean (SD) age 66 (11) years) with high rate, drug resistant paroxysmal atrial fibrillation (308) or chronic atrial fibrillation (277). Lone atrial fibrillation was present in 133 patients, while the remaining 452 suffered from dilated, ischaemic, or valvar heart disease. Patients underwent VVIR (454) or DDDR (131) pacemaker implantation, after AV node ablation. Antiplatelet agents were given to 202 patients, warfarin to 187 patients. RESULTS: During a follow up of 33.6 (24.2) months, thromboembolic events were observed in 17 patients (3%); the actuarial occurrence rates of thromboembolism were 1.1%, 3%, 4.2%, and 7.4% after one, three, five, and seven years, respectively. Among five variables, univariate analysis showed that only the presence of chronic atrial fibrillation at the time of ablation (relative risk (RR) = 1.8, 95% confidence interval (CI) = 1.02 to 3. 20, p = 0.04) and the need for warfarin treatment (RR = 1.6, 95% CI 1.00 to 2.71, p = 0.048) were associated with a significantly higher risk of occurrence of thromboembolic events. On multivariate analysis the only predictor of embolic events during the follow up was the presence of chronic atrial fibrillation. CONCLUSIONS: Data from this large cohort of patients indicate a fairly low incidence (1.04% per year) of thromboembolic events after AV node ablation and pacing for drug refractory, high rate atrial fibrillation.

Aged↗

Risk of thromboembolism during diagnostic and interventional cardiac procedures with nonionic contrast media.

To investigate the relationship between clot formation and thromboembolism, canine blood was withdrawn into catheter-syringe or catheter-steerable wire systems containing either contrast medium or normal saline as used in debubbling techniques. The contrast media used were iohexol, iopamidol, ioxaglate, and diatrizoate. Without the use of heparin, after a 30-minute incubation, blood clots were harvested from all catheter-syringe systems except those with diatrizoate and from all catheter-steerable wire systems. Significantly more blood clot was harvested from the catheter-steerable wire system. With use of heparinized blood, no clot was found in any system. Twelve dogs that underwent coronary angiography were divided into two groups; one received heparin (5,000 IU) and the other did not. Thromboembolism occurred in all nonheparinized dogs that underwent angiography with iohexol or iopamidol but not in any other group. The authors found that in a dog model nonionic contrast media are more thrombogenic than ionic contrast media, especially in the catheter-steerable wire system. The blood clot in the catheters is associated with thromboembolism during angiography. The authors maintain that in this setting, blood clotting and thromboembolism with nonionic agents can be eliminated with heparin.

Animals↗

[Effect of hyperhomocysteinemia and methylenetetrahydrofolate reductase 677C --> T mutation in venous thromboembolism risk of young adults].

BACKGROUND AND OBJECTIVE: To investigate whether hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) 677C --> T mutation are associated with venous thromboembolism in young Spanish adults. PATIENTS AND METHOD: One hundred adult patients younger than 50 years and 177 controls with similar age and gender. RESULTS: Hyperhomocysteinemia was present in 21% of the patients and 3.3% of the controls (p < 0.001), and MTHFR 677C --> T mutation was found in 25 and 14.7%, respectively (p = 0.03). Odds ratio (OR) for thromboembolism in hyperhomocysteinemic patients was 7.5 (95% CI, 2.9-19.2; p < 0.001), and in patients with MTHFR 677C --> T mutation the OR was 1.9 (95% CI, 1.1-3.5; p = 0.03). In a subgroup of 76 patients without other thrombogenic factors, thromboembolism persisted associated with hyperhomocysteinemia, yet an association with MTHFR 677C --> T mutation was not confirmed. CONCLUSIONS: Hyperhomocysteinemia, but not MTHFR 677C --> T mutation, is a risk factor for venous thromboembolism in young adults without other thrombogenic factors.

Adult↗

Thromboembolic complications of intravenous immunoglobulin treatment.

Intravenous immunoglobulin (IVIg) preparations are increasingly being used in the treatment of neuroautoimmune diseases. Although for most part this treatment is safe, serious side effects such as thromboembolic events have been reported. We report on 7 patients who suffered a thromboembolic event while being treated with IVIg. Four patients suffered a stroke or transient ischemic attack, 1 an inferior wall myocardial infarction, 1 a deep venous thrombosis, and 1 a retinal artery infarct. The age range of the patients was 57-81 and most had underlying risk factors, such as hypertension, hypercholesterolemia, atrial fibrillation, history of vascular disease and stroke, and deep venous thrombosis. Three patients received multiple IVIg infusions before suffering a thromboembolic complication. Therefore, the clinicians should be vigilant about the possibility of thromboembolic complications with each IVIg infusion and be especially judicious with the use of IVIg in patients with underlying risk factors.

Aged↗

Plasma homocysteine in venous thromboembolism.

Severe hyperhomocysteinemia due to inborn errors of methionine metabolism results in precocious development of arteriosclerosis and predisposition to venous and arterial thromboembolism. Although the findings of several studies have indicated that mild hyperhomocysteinemia is common in occlusive arterial disease, no similar studies have been made on venous thromboembolism. In this study of subjects under 50 years of age, we found no significant differences in the plasma homocysteine concentrations, either in the fasting state or after methionine loading, between 42 patients with venous thromboembolism and 42 healthy controls. Nonetheless, male patients manifested a tendency toward higher homocysteine concentrations than male controls; 6 patients (14%) versus 2 controls (5%) responded abnormally to methionine loading which might indicate heterozygosity for cystathionine synthase deficiency. Thus, further studies on plasma homocysteine in venous thromboembolism are warranted.

Adult↗

Is prolonged immobilization a risk factor for symptomatic venous thromboembolism in elderly bedridden patients? Results of a historical-cohort study.

Prolonged immobilization and advanced age are considered to be important risk factors for venous thromboembolism (VTE). Nevertheless, the need for VTE prophylaxis in long-term bedridden patients is not known. To assess whether very prolonged immobilization (i.e. over three months) carries an increased risk for clinically apparent VTE, we performed a historical-cohort study of nursing home residents during a ten-year period. Data concerning patient's mobility and incidence of overt deep vein thrombosis or pulmonary embolism were registered. The mean resident age was 85+/-8.4 years. Eighteen mobile and eight immobile patients were diagnosed with clinically significant thromboembolic events, during 1137 and 573 patient-years of follow up, respectively. The incidence of venous thromboembolic events was similar in both chronically immobilized and mobile patient groups, 13.9 and 15.8 per thousand patient years, respectively (p=0.77). The rate ratio for having a VTE event in the immobilized patient group as compared with the mobile group was 0.88 (95% Confidence Interval (CI) 0.33 to 2.13). When taking into account baseline characteristics, risk factors and death rates by various causes, no differences were found between the two groups. In conclusion, chronically immobile bedridden patients are no more prone to clinically overt venous thromboembolic events than institutionalized mobile patients. Until further studies are performed concerning the impact of very prolonged immobilization on the risk of VTE, there is no evidence to support primary prevention after the first three months of immobilization. Evidence for efficacy or cost effectiveness beyond this early period is not available.

Aged↗

Postmenopausal hormone replacement and venous thromboembolism following hip and knee arthroplasty.

Hormone replacement therapy has been associated with venous thromboembolism. Controversy exists regarding the appropriate management of hormone replacement in the perioperative setting and in other situations--such as acute illness--predisposing to acute venous thromboembolism. We performed a case-control study to determine whether perioperative hormone replacement is associated with venous thromboembolism following hip and knee arthroplasty. 108 patients with postoperative venous thrombosis were matched by age, date and type of surgery, and surgeon with 210 controls without thrombosis. Perioperative hormone replacement use was no more prevalent in patients with postoperative thrombosis than those without. Eighteen (16.7%) women with post-operative thrombosis had taken perioperative hormone replacement compared to 49 (23.3%) of controls: odds ratio = 0.66; (95% CI 0.35-1.18; p=0.17). After multivariate analysis, the adjusted odds ratios were similar. Variables predicting post-operative thrombosis included: prior venous thromboembolism (OR = 2.3; p = 0.02), rheumatologic disease (OR = 2.2; p = 0.03), and absence of pharmacologic antithrombotic prophylaxis (OR = 13.4; p = 0.005). Cases and controls were otherwise similar. Users of hormone replacement were similar to non-users except that they were less likely to have coronary disease (OR 0.34; p = 0.03) or prior thrombosis (OR = 0.28; p = 0.04), and were younger (median age 67 versus 74 years; p <0.0001). We found no association between perioperative hormone replacement and post-operative thrombosis in patients undergoing major orthopaedic surgery. Routine discontinuation of these medications preoperatively--and possibly in other situations predisposing to thrombosis, such as acute medical illness--may be unnecessary in patients receiving appropriate pharmacologic antithrombotic prophylaxis.

Acute Disease↗

Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.

BACKGROUND: Considerable variability exists in the use of pharmacological thromboprophylaxis among acutely ill medical patients, partly because clinically relevant end points have not been fully assessed in this population. We undertook an international, multicenter, randomized, double-blind, placebo-controlled trial using clinically important outcomes to assess the efficacy and safety of dalteparin in the prevention of venous thromboembolism in such patients. METHODS AND RESULTS: Patients (n=3706) were randomly assigned to receive either subcutaneous dalteparin 5000 IU daily or placebo for 14 days and were followed up for 90 days. The primary end point was venous thromboembolism, defined as the combination of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, and asymptomatic proximal deep vein thrombosis detected by compression ultrasound at day 21 and sudden death by day 21. The incidence of venous thromboembolism was reduced from 4.96% (73 of 1473 patients) in the placebo group to 2.77% (42 of 1518 patients) in the dalteparin group, an absolute risk reduction of 2.19% or a relative risk reduction of 45% (relative risk, 0.55; 95% CI, 0.38 to 0.80; P=0.0015). The observed benefit was maintained at 90 days. The overall incidence of major bleeding was low but higher in the dalteparin group (9 patients; 0.49%) compared with the placebo group (3 patients; 0.16%). CONCLUSIONS: Dalteparin 5000 IU once daily halved the rate of venous thromboembolism with a low risk of bleeding.

Acute Disease↗