Judging the safety of aprotinin.
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Advisory Committees↗
Biomedical subjects
Dennis T Mangano
Publications and source records attributed to Dennis T Mangano.
Post-reperfusion myocardial infarction: long-term survival improvement using adenosine regulation with acadesine.
OBJECTIVES: The purpose of this study was to assess the safety and efficacy of the adenosine regulating agent (ARA) acadesine for reducing long-term mortality among patients with post-reperfusion myocardial infarction (MI). BACKGROUND: No prospectively applied therapy exists that improves long-term survival after MI associated with coronary artery bypass graft (CABG) surgery-a robust model of ischemia/reperfusion injury. Pretreatment with the purine nucleoside autocoid adenosine mitigates the extent of post-ischemic reperfusion injury in animal models. Therefore, we questioned whether use of the ARA acadesine-by increasing interstitial adenosine concentrations in ischemic tissue-would improve long-term survival after post-reperfusion MI. METHODS: At 54 institutions, 2,698 patients undergoing CABG surgery were randomized to receive placebo (n = 1,346) or acadesine (n = 1,352) by intravenous infusion (0.1 mg/kg/min; 7 h) and in cardioplegia solution (placebo or acadesine; 5 microg/ml). Myocardial infarction was prospectively defined as: 1) new Q-wave and MB isoform of creatine kinase (CK-MB) elevation (daily electrocardiography; 16 serial CK-MB measurements); or 2) autopsy evidence. Vital status was assessed over 2 years, and outcomes were adjudicated centrally. RESULTS: Perioperative MI occurred in 100 patients (3.7%), conferring a 4.2-fold increase in 2-year mortality (p < 0.001) compared with those not suffering MI. Acadesine treatment, however, reduced that mortality by 4.3-fold, from 27.8% (15 of 54; placebo) to 6.5% (3 of 46; acadesine) (p = 0.006), with the principal benefit occurring over the first 30 days after MI. The acadesine benefit was similar among diverse subsets, and multivariable analysis confirmed these findings. CONCLUSIONS: Acadesine is the first therapy proven to be effective for reducing the severity of acute post-reperfusion MI, substantially reducing the risk of dying over the 2 years after infarction.
Adenosine↗
The risk associated with aprotinin in cardiac surgery.
BACKGROUND: The majority of patients undergoing surgical treatment for ST-elevation myocardial infarction receive antifibrinolytic therapy to limit blood loss. This approach appears counterintuitive to the accepted medical treatment of the same condition--namely, fibrinolysis to limit thrombosis. Despite this concern, no independent, large-scale safety assessment has been undertaken. METHODS: In this observational study involving 4374 patients undergoing revascularization, we prospectively assessed three agents (aprotinin [1295 patients], aminocaproic acid [883], and tranexamic acid [822]) as compared with no agent (1374 patients) with regard to serious outcomes by propensity and multivariable methods. (Although aprotinin is a serine protease inhibitor, here we use the term antifibrinolytic therapy to include all three agents.) RESULTS: In propensity-adjusted, multivariable logistic regression (C-index, 0.72), use of aprotinin was associated with a doubling in the risk of renal failure requiring dialysis among patients undergoing complex coronary-artery surgery (odds ratio, 2.59; 95 percent confidence interval, 1.36 to 4.95) or primary surgery (odds ratio, 2.34; 95 percent confidence interval, 1.27 to 4.31). Similarly, use of aprotinin in the latter group was associated with a 55 percent increase in the risk of myocardial infarction or heart failure (P<0.001) and a 181 percent increase in the risk of stroke or encephalopathy (P=0.001). Neither aminocaproic acid nor tranexamic acid was associated with an increased risk of renal, cardiac, or cerebral events. Adjustment according to propensity score for the use of any one of the three agents as compared with no agent yielded nearly identical findings. All the agents reduced blood loss. CONCLUSIONS: The association between aprotinin and serious end-organ damage indicates that continued use is not prudent. In contrast, the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives.
Adult↗
Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery.
OBJECTIVE: Statin therapy in ambulatory populations is associated with a significant reduction in adverse cardiovascular events, including death and myocardial infarction. Much less is known about the beneficial effects of statins on acute perioperative cardiovascular events. The purpose of this study was to determine whether preoperative statin therapy is associated with a reduced risk of early cardiac death or nonfatal, in-hospital postoperative myocardial infarction after primary, elective coronary artery bypass graft surgery requiring cardiopulmonary bypass. METHODS: The Multicenter Study of Perioperative Ischemia (McSPI) Epidemiology II Study was a prospective, longitudinal study of 5436 patients undergoing coronary artery bypass graft surgery between November 1996 and June 2000 at 70 centers in 17 countries. The present study consisted of a pre-specified subset of these subjects divided into patients receiving (n = 1352) and not receiving (n = 1314) preoperative statin therapy. To control for potential bias related to use of statin therapy, the study estimated propensity scores by logistic regression to determine the predicted probability of inclusion in the "statin" group. Multivariate, stepwise logistic regression was then performed, controlling for patient demographics, medical history, operative characteristics, and propensity score to determine whether preoperative statin therapy was independently associated with a reduction in the risk of early (DOS-POD3) cardiac death and/or nonfatal, in-hospital postoperative myocardial infarction. RESULTS: Preoperative statin therapy was independently associated with a significant reduction (adjusted odds ratio [OR] 0.25; 95% confidence intervals [CI] 0.07-0.87) in the risk of early cardiac death after primary, elective coronary bypass surgery (0.3% vs 1.4%; P < .03), but was not associated with a reduced risk of postoperative nonfatal, in-hospital myocardial infarction (7.9% vs 6.2%; P = not significant). Discontinuation of statin therapy after surgery was independently associated with a significant increase in late (POD4-discharge) all-cause mortality (adjusted OR 2.64; 95% CI 1.32-5.26) compared with continuation of statin therapy (2.64% vs 0.60%; P < .01). This was true even when controlling for the postoperative discontinuation of aspirin, beta-blocker, or angiotensin-converting enzyme inhibitor therapy. Discontinuation of statin therapy after surgery was also independently associated with a significant increase in late cardiac mortality (adjusted OR 2.95; 95% CI 1.31-6.66) compared with continuation of statin therapy (1.91% vs 0.45%; P < 0.01). CONCLUSIONS: Preoperative statin use is associated with reduced cardiac mortality after primary, elective coronary artery bypass grafting. Postoperative statin discontinuation is associated with increased in-hospital mortality. Although further randomized trials are needed to confirm these findings, these data suggest the importance of perioperative statin administration.
Cardiopulmonary Bypass↗
Hormone replacement therapy is safe in women undergoing coronary artery bypass grafting.
In postmenopausal women, hormone replacement therapy (HRT) does not substantially reduce the incidence of cardiovascular disease and may produce a short-term increase in risk. Therefore, we investigated whether HRT increased risk in patients with severe coronary artery disease necessitating surgery We prospectively studied 4,782 patients undergoing coronary artery bypass grafting at 70 centers in 17 countries from November 1996 through June 2000. Patients were selected using a systematic sampling technique. Mortality, major morbidity, and transfusion requirements were compared among 3 groups: men (n=3,840), women receiving HRT (n= 144), and women not receiving HRT (n=798). Women actively receiving HRT, compared with women not receiving HRT or with men, were at no greater risk of developing the following fatal or non-fatal complications: death (2.8% vs 4.4% vs 2.8%, respectively; P=0.05), myocardial infarction (6.3% vs 7.0% vs 7.7%; P=0.67), central nervous system complication (2.1% vs 2.8% vs 2.9%; P=0.85), or renal dysfunction (0.7% vs 5.3% vs 4.8%; P=0.06). Incidence of postoperative congestive heart failure was significantly lower in men (7.7%) than in women receiving HRT (12.5%; P=0.04) and in women without HRT (12.8%; P <0.0001). Fewer men (61%) needed red blood cell transfusion than did women receiving HRT (79%) and women without HRT (88%) (P <0.0001 compared with both other groups). However, the need for fresh frozen plasma transfusions was significantly less in women receiving HRT (16%) than in women not receiving HRT (25%; P=0.01). We conclude that HRT administration before coronary artery bypass grafting does not increase women's risk of any adverse outcome.
Aged↗
A multicenter risk index for atrial fibrillation after cardiac surgery.
CONTEXT: Atrial fibrillation is a common, but potentially preventable, complication following coronary artery bypass graft (CABG) surgery. OBJECTIVES: To assess the nature and consequences of atrial fibrillation after CABG surgery and to develop a comprehensive risk index that can better identify patients at risk for atrial fibrillation. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study of 4657 patients undergoing CABG surgery between November 1996 and June 2000 at 70 centers located within 17 countries, selected using a systematic sampling technique. From a derivation cohort of 3093 patients, associations between predictor variables and postoperative atrial fibrillation were identified to develop a risk model, which was assessed in a validation cohort of 1564 patients. MAIN OUTCOME MEASURE: New-onset atrial fibrillation after CABG surgery. RESULTS: A total of 1503 patients (32.3%) developed atrial fibrillation after CABG surgery. Postoperative atrial fibrillation was associated with subsequent greater resource use as well as with cognitive changes, renal dysfunction, and infection. Among patients in the derivation cohort, risk factors associated with atrial fibrillation were advanced age (odds ratio [OR] for 10-year increase, 1.75; 95% confidence interval [CI], 1.59-1.93); history of atrial fibrillation (OR, 2.11; 95% CI, 1.57-2.85) or chronic obstructive pulmonary disease (OR, 1.43; 95% CI, 1.09-1.87); valve surgery (OR, 1.74; 95% CI, 1.31-2.32); and postoperative withdrawal of a beta-blocker (OR, 1.91; 95% CI, 1.52-2.40) or an angiotensin-converting enzyme (ACE) inhibitor (OR 1.69; 95% CI, 1.38-2.08). Conversely, reduced risk was associated with postoperative administration of beta-blockers (OR, 0.32; 95% CI, 0.22-0.46), ACE inhibitors (OR, 0.62; 95% CI, 0.48-0.79), potassium supplementation (OR, 0.53; 95% CI, 0.42-0.68), and nonsteroidal anti-inflammatory drugs (OR, 0.49; 95% CI, 0.40-0.60). The resulting multivariable risk index had adequate discriminative power with an area under the receiver operating characteristic (ROC) curve of 0.77 in the validation sample. Forty-three percent (640/1503) of patients who had atrial fibrillation after CABG surgery experienced more than 1 episode of atrial fibrillation. Predictors of recurrent atrial fibrillation included older age, history of congestive heart failure, left ventricular hypertrophy, aortic atherosclerosis, bicaval venous cannulation, withdrawal of ACE inhibitor or beta-blocker therapy, and use of amiodarone or digoxin (area under the ROC curve of 0.66). Patients with recurrent atrial fibrillation had longer hospital stays and experienced greater infectious, renal, and neurological complications than those with a single episode. CONCLUSIONS: We have developed and validated models predicting the occurrence of atrial fibrillation after CABG surgery based on an analysis of a large multicenter international cohort. Our findings suggest that treatment with beta-blockers, ACE inhibitors, and/or nonsteroidal anti-inflammatory drugs may offer protection. Atrial fibrillation after CABG surgery is associated with important complications.
Aged↗
Impact of pexelizumab, an anti-C5 complement antibody, on total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary bypass.
BACKGROUND: During cardiac surgery requiring cardiopulmonary bypass, pro-inflammatory complement pathways are activated by exposure of blood to bio-incompatible surfaces of the extracorporeal circuit and reperfusion of ischemic organs. Complement activation promotes the generation of additional inflammatory mediators thereby exacerbating tissue injury. We examined the safety and efficacy of a C5 complement inhibitor for attenuating inflammation-mediated cardiovascular dysfunction in cardiac surgical patients undergoing cardiopulmonary bypass. METHODS: Pexelizumab (Alexion Pharmaceuticals, Inc, Cheshire, CT), a recombinant, single-chain, anti-C5 monoclonal antibody, was evaluated in a randomized, double-blinded, placebo-controlled, multicenter trial that involved 914 patients undergoing coronary artery bypass grafting with or without valve surgery requiring cardiopulmonary bypass. RESULTS: Pexelizumab was administered intravenously as a bolus (2.0 mg/kg) or bolus plus infusion (2.0 mg/kg plus 0.05 mg/kg/h for 24 hours), and inhibited complement activation. There were no statistically significant differences between placebo-treated and pexelizumab-treated patients in the primary endpoint (composite of death, or new Q-wave, or non-Q-wave [myocardial-specific isoform of creatine kinase > 60 ng/mL] myocardial infarction, or left ventricular dysfunction, or new central nervous system deficit). However, post hoc analysis revealed a reduction in the composite of death or myocardial infarction (myocardial-specific isoform of creatine kinase >/= 100 ng/mL) for the isolated coronary artery bypass grafting, bolus plus infusion subgroup on POD 4 (p = 0.007) and on POD 30 (p = 0.004). CONCLUSIONS: Pexelizumab had no statistically significant effect on the primary endpoint. However, the reduction in death or myocardial infarction (myocardial-specific isoform of creatine kinase >/= 100 ng/mL) as revealed in the post hoc analysis in the isolated coronary artery bypass grafting bolus plus infusion subpopulation, suggests that further investigation of anti-C5 therapy for ameliorating complement-mediated inflammation and myocardial injury is warranted.
Antibodies, Monoclonal↗
Perioperative medicine: NHLBI working group deliberations and recommendations.
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Health Education↗
Adverse gastrointestinal complications after cardiopulmonary bypass: can outcome be predicted from preoperative risk factors?
UNLABELLED: Adverse gastrointestinal (GI) outcome after cardiac surgery is an infrequent event but is a clinically important health care problem because of associated increased morbidity and mortality. The ability to identify patients at greatest risk before surgery may be helpful in planning appropriate perioperative management strategies. We examined the pre- and intraoperative characteristics of 2417 patients from 24 diverse United States medical centers enrolled in the Multicenter Study of Perioperative Ischemia Study who were undergoing cardiac surgery using cardiopulmonary bypass as predictors for adverse GI outcome. Resource utilization was evaluated for patients with and without adverse GI outcomes. Adverse GI outcomes occurred in 5.5% of patients (133 of 2417), increased in-hospital mortality 6.5-fold, prolonged the mean intensive care unit length of stay by 1 wk, and more than doubled the mean postoperative hospital stay (P < 0.0001). Predictors of adverse GI outcome included decreased left ventricular function, hyperbilirubinemia, thrombocytopenia, prolonged partial thromboplastin time, prior cardiovascular surgery, combined coronary artery bypass graft surgery and intracardiac or proximal aortic surgery, pharmacological cardiovascular support, and intraoperative transfusion. The literature suggests that adverse GI outcome after cardiac surgery is secondary to poor splanchnic perfusion, which many of these risk factors may predict. Therefore, patients deemed to be at risk before surgery may benefit from tightly controlled hemodynamic management and other strategies that optimize perioperative organ perfusion. IMPLICATIONS: We identified the preoperative and intraoperative predictors associated with an increased incidence of postoperative gastrointestinal complications after cardiac surgery using cardiopulmonary bypass. Because these complications are associated with frequent morbidity and mortality, these predictors may be helpful in identifying patients at increased risk so that risk stratification can be modified and perioperative management can be appropriately adjusted.
Aged↗
Pulmonary-artery catheters in high-risk surgical patients.
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Cardiac Surgical Procedures↗
Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery.
OBJECTIVE: Inhibition of cyclooxygenase 2 provides analgesia in ambulatory patients. We prospectively evaluated the safety and efficacy of a newly introduced cyclooxygenase 2 inhibitor in patients undergoing coronary artery bypass grafting surgery through a median sternotomy in a randomized clinical trial. METHODS: A total of 462 patients with New York Heart Association classes I to III who were less than 77 years of age and were from 58 institutions in the United States, Canada, Germany, and the United Kingdom participated in this multicenter, phase III, placebo-controlled, double-blind, randomized, parallel-group trial. Patients were allocated at a ratio of 2:1 to parecoxib/valdecoxib or standard care (control) groups, respectively. Intravenous study drug (40 mg) was administered within 30 minutes after extubation and every 12 hours for a minimum of 3 days. Subsequently, oral treatment at a dose of 40 mg every 12 hours was initiated and administered for a combined total of 14 days. Patient-controlled analgesia with morphine, oral opioids, or acetaminophen was available as required. Assessment of the analgesic efficacy of the study drug was primarily based on morphine and morphine equivalent use. Additional efficacy evaluations included daily pain intensity, patient and physician global evaluation of study medication, and pain effect on quality of life. Clinical adverse events were assessed by the principal investigator at each site from the time of the first dose through the 30-day postdosing period. RESULTS: Patients in the parecoxib/valdecoxib group received significantly less morphine or morphine equivalents than patients in the control group during the 0- to 24-hour (P =.009), 24- to 48-hour (P =.017), 72- to 96-hour (P =.002), 96- to 120-hour (P =.004), and 120- to 144-hour (P =.037) periods. Both patients (P <.001) and physicians (P <.001) evaluated the study medication as significantly better than control therapy. The modified Brief Pain Inventory questionnaire used in the oral dosing period detected significant improvements in the parecoxib/valdecoxib treatment group in 6 of 8 domains tested (eg, current pain, worst pain, and mood) beginning on day 4 and continuing for at least 4 days. Although there were no differences between the groups in overall adverse events, serious adverse events occurred twice as frequently in parecoxib/valdecoxib-treated patients (19.0%, 59/311 patients) than in control patients (9.9%, 15/151 patients; P =.015). Regarding individual serious adverse events, a greater incidence in sternal wound infection was found in the parecoxib/valdecoxib patients (10 [3.2%]) versus control patients (0 [0%]) (P =.035). The incidences of other individual serious adverse events, including cerebrovascular complications, myocardial infarction, and renal dysfunction, were proportionally greater but not significantly different between the groups. CONCLUSIONS: In patients undergoing coronary artery bypass grafting surgery, the cyclooxygenase 2 inhibitor combination, parecoxib/valdecoxib, was effective for postoperative analgesia. However, the 14-day treatment regimen also was associated with an increased incidence of serious adverse events overall and sternal wound infections in particular. Therefore our study raises important concerns requiring their comprehensive evaluation in a large-scale trial before these cyclooxygenase 2 inhibitors are used in patients undergoing coronary artery bypass grafting surgery.
Administration, Oral↗
Prevalence of risk factors, and not gender per se, determines short- and long-term survival after coronary artery bypass surgery.
OBJECTIVE: Much attention has been directed towards female gender as an independent risk factor for in-hospital mortality after coronary artery bypass grafting surgery; however, the effects of surgery are known to persist for 6 months or more. Studies that have compared postoperative survival in women and men beyond hospital discharge report disparate results with regard to the independent effect of gender per se on ultimate survival. DESIGN: This investigation was a prospective, observational study. SETTING: The study was a multicenter investigation involving 24 US medical centers. PARTICIPANTS: There were 2,048 patients undergoing isolated coronary artery bypass graft surgery enrolled between September 1991 and September 1993 and after discharge. INTERVENTIONS: There were no interventions with this prospective observational study. MEASUREMENTS AND MAIN RESULTS: Preoperative demographic variables, medical history, and angiographic data were collected for each patient at the time of enrollment. Patients' vital status through the National Death Index up to August 31, 1998, were added to assess postoperative long-term survival. For survivorship analysis, the Kaplan-Meier product-limit method was used with Cox regression model. Survivorship analyses were performed separately and in combination on mortality within 30 days and 6 months of coronary artery bypass graft surgery and during the entire postoperative follow-up period. Among women, preoperative disease status, as expected, was more severe than that in men. Women were older (p = 0.0001) and had more comorbidity, such as congestive heart failure (p = 0.0019), diabetes (p = 0.0001), anemia, and hypertension (p = 0.0001). After surgery, unadjusted survival of 6 months and 5 years in women was worse than that in men. However, there were no gender-related differences in short- or long-term survival after adjusting for covariates in the multivariate model. Preoperative conditions, such as congestive heart failure, anemia, diabetes, and advanced age, are indicative of greater risk in both women and men for lower survival after coronary artery bypass graft surgery. CONCLUSIONS: Disease prevalence in women, and not gender per se, affects mid- and long-term survival after cardiac surgery. Attention, therefore, should be focused on efforts to reduce or modify such disease prevalence earlier in women, which may in turn allow longer survival after surgical intervention. Differences in postoperative survival between women and men were related to the gender differences in the distribution of preoperative risk factors.
Aged↗
S100beta and NSE: stroke surrogate signals or natal neural noise?
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Biomarkers↗
Aspirin and mortality from coronary bypass surgery.
BACKGROUND: There is no therapy known to reduce the risk of complications or death after coronary bypass surgery. Because platelet activation constitutes a pivotal mechanism for injury in patients with atherosclerosis, we assessed whether early treatment with aspirin could improve survival after coronary bypass surgery. METHODS: At 70 centers in 17 countries, we prospectively studied 5065 patients undergoing coronary bypass surgery, of whom 5022 survived the first 48 hours after surgery. We gathered data on 7500 variables per patient and adjudicated outcomes centrally. The primary focus was to discern the relation between early aspirin use and fatal and nonfatal outcomes. RESULTS: During hospitalization, 164 patients died (3.2 percent), and 812 others (16.0 percent) had nonfatal cardiac, cerebral, renal, or gastrointestinal ischemic complications. Among patients who received aspirin (up to 650 mg) within 48 hours after revascularization, subsequent mortality was 1.3 percent (40 of 2999 patients), as compared with 4.0 percent among those who did not receive aspirin during this period (81 of 2023, P<0.001). Aspirin therapy was associated with a 48 percent reduction in the incidence of myocardial infarction (2.8 percent vs. 5.4 percent, P<0.001), a 50 percent reduction in the incidence of stroke (1.3 percent vs. 2.6 percent, P=0.01), a 74 percent reduction in the incidence of renal failure (0.9 percent vs. 3.4 percent, P<0.001), and a 62 percent reduction in the incidence of bowel infarction (0.3 percent vs. 0.8 percent, P=0.01). Multivariate analysis showed that no other factor or medication was independently associated with reduced rates of these outcomes and that the risk of hemorrhage, gastritis, infection, or impaired wound healing was not increased with aspirin use (odds ratio for these adverse events, 0.63; 95 percent confidence interval, 0.54 to 0.74). CONCLUSIONS: Early use of aspirin after coronary bypass surgery is safe and is associated with a reduced risk of death and ischemic complications involving the heart, brain, kidneys, and gastrointestinal tract.
Aged↗
Practice pattern variability for myocardial revascularization: impact on resource use across 24 centers.
OBJECTIVE: To determine the predictors of hospital length of stay (LOS) after elective uncomplicated coronary artery bypass graft surgery. DESIGN: Retrospective analysis of the EPI-1 database, 1991-1993. SETTING: Multicenter; 24 academic, private, federal, and health maintenance institutions. PARTICIPANTS: Patients undergoing elective CABG surgery (n = 2,417). MEASUREMENTS AND MAIN RESULTS: Using a systematic sampling scheme at each site, each patient was evaluated to identify markers of chronic disease, perioperative test data, treatments, adverse outcomes, and LOS. Institutional differences in the care of patients free of complications were assessed using a multivariate model. LOS was the outcome variable selected to estimate cost. A total of 861 patients (37%) were free of any complication. The mean site LOS ranged from 5.4 to 9.0 days, with half of the 24 centers reporting a hospital LOS routinely >7.1 days. The predominant factor associated with a complication-free LOS was site per se, accounting for 32% of the variability in hospital LOS that could not be explained by any site characteristic (eg, size, geographic location, academic affiliation). Multivariable analysis identified 3 demographic predictors--age >75 years (increasing LOS by 1.3 days), admission from the emergency department (increasing LOS by 0.7 days), and uninsured or Medicaid-insured (increasing LOS by 0.4 days); 2 historical predictors--New York Heart Association class III or IV congestive heart failure (increasing LOS by 0.5 days) and history of arrhythmia (increasing LOS by 0.7 days); and 2 practice patterns--transfusion of blood products (increasing LOS by 0.3 days) and delayed extubation (increasing LOS by 0.5 days). Previous myocardial infarction, diabetes, chronic obstructive pulmonary disease, neurologic disease, and other historical factors were not associated with LOS in patients without a complication. CONCLUSION: A substantial variability in LOS after complication-free coronary artery bypass graft surgery was determined predominantly by site per se, even after adjustment for disease severity, site type or location, and surgical and anesthetic practices. The variability in LOS was likely due to practice style influences and represents an opportunity to decrease waste in the provision of a common and expensive procedure.
Blood Transfusion↗