Adrenergic receptor genotype but not perioperative bisoprolol therapy may determine cardiovascular outcome in at-risk patients undergoing surgery with spinal block: the Swiss Beta Blocker in Spinal Anesthesia (BBSA) study: a double-blinded, placebo-controlled, multicenter trial with 1-year follow-up

BACKGROUND: Neuraxial blockade is used as primary anesthetic technique in one third of surgical procedures. The authors tested whether bisoprolol would protect patients at risk for cardiovascular complications undergoing surgery with spinal block. METHODS: The authors performed a double-blinded, placebo-controlled, multicenter trial to compare the effect of bisoprolol with that of placebo on 1-yr composite outcome including cardiovascular mortality, nonfatal myocardial infarction, unstable angina, congestive heart failure, and cerebrovascular insult. Bisoprolol was given orally before and after surgery for a maximum of 10 days. Adrenergic receptor polymorphisms and safety outcome measures of bisoprolol therapy were also determined. RESULTS: A total of 224 patients were enrolled. Spinal block could not be established in 5 patients. One hundred ten patients were assigned to the bisoprolol group, and 109 patients were assigned to the placebo group. The mean duration of treatment was 4.9 days in the bisoprolol group and 5.1 days in the placebo group. Bisoprolol therapy reduced mean heart rate by 10 beats/min. The primary outcome was identical between treatment groups and occurred in 25 patients (22.7%) in the bisoprolol group and 24 patients (22.0%) in the placebo group during the 1-yr follow-up (hazard ratio, 0.97; 95% confidence interval, 0.55-1.69; P = 0.90). However, carriers of at least one Gly allele of the beta1-adrenergic receptor polymorphism Arg389Gly showed a higher number of adverse events than Arg homozygous (32.4% vs. 18.7%; hazard ratio, 1.87; 95% confidence interval, 1.04-3.35; P = 0.04). CONCLUSIONS: Perioperative bisoprolol therapy did not affect cardiovascular outcome in these elderly at-risk patients undergoing surgery with spinal block.     

Acute limb ischemia in elderly patients: can iloprost be useful as an adjuvant to surgery? Results from the ILAILL study.

OBJECTIVES: To evaluate the effects of iloprost, in addition to surgery, on the outcome of acute lower limb ischemia (ALLI). DESIGN: Post-hoc analysis of a randomized, double-blind, placebo-controlled study. METHODS: In the context of the ILAILL (ILoprost in Acute Ischemia of Lower Limbs) study, 192 elderly patients (>70 years old) undergoing surgery for ALLI were assigned to receive perioperative iloprost (intra-arterial, intra-operative bolus of 3000 ng, plus intravenous infusion of 0.5-2.0 ng/kg/min for six hours/day for 4-7 days following surgery), or placebo (iloprost: n=100; placebo: n=92). Patients were followed-up for three-months following surgical revascularization. RESULTS: The combined incidence of death and amputation (primary study end-point) was significantly reduced in patients treated with iloprost (16.0% vs 27.2% in the placebo group; hazard ratio 1.99, 95% confidence interval 1.05-3.75, p=0.03). A statistically significant lower mortality (6.0%) was reported in patients receiving iloprost, compared to controls (15.2%) (hazard ratio 2.93, 1.11-7.71, p=0.03). The overall incidence of death and major cardiovascular events was lower in patients receiving iloprost compared to those assigned placebo (24.0% and 35.9%, respectively), at the limits of statistical significance (relative risk 1.64, 0.97-2.79, p=0.06). CONCLUSIONS: These results confirm the poor outcome in elderly patients with ALLI. Based on a subgroup analysis iloprost, as an adjuvant to surgery, appears to reduce the combined end-point of death and amputation.     

Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial

OBJECTIVE: To assess whether a pragmatic policy of perioperative beta-blockade, with metoprolol, reduced the 30-day cardiovascular morbidity and mortality and reduced the length of hospital stay in average patients undergoing infrarenal vascular surgery. METHODS: This was a double-blind randomized placebo-controlled trial that occurred in vascular surgical units in four UK hospitals. Participants were 103 patients without previous myocardial infarction who had infrarenal vascular surgery between July 2001 and March 2004. Interventions were oral metoprolol (50 mg twice daily, supplemented by intravenous doses when necessary) or placebo from admission until 7 days after surgery. Holter monitors were kept in place for 72 hours after surgery. RESULTS: Eighty men and 23 women (median age, 73 years) were randomized, 55 to metoprolol and 48 to placebo, and 97 (94%) underwent surgery during the trial. The most common operations were aortic aneurysm repair (38%) and distal bypass (29%). Intraoperative inotropic support was required in 64% and 92% of patients in the placebo and metoprolol groups, respectively. Within 30 days, cardiovascular events occurred in 32 patients, including myocardial infarction (8%), unstable angina (9%), ventricular tachycardia (19%), and stroke (1%). Four (4%) deaths were reported. Cardiovascular events occurred in 15 (34%) and 17 (32%) patients in the placebo and metoprolol groups, respectively (unadjusted relative risk, 0.94; 95% confidence interval, 0.53-1.66; adjusted [for age, sex, statin use, and aortic cross-clamping] relative risk, 0.87; 95% confidence interval, 0.48-1.55). Time from operation to discharge was reduced from a median of 12 days (95% confidence interval, 9-19 days) in the placebo group to 10 days (95% confidence interval, 8-12 days) in the metoprolol group (adjusted hazard ratio, 1.71; 95% confidence interval, 1.09-2.66; P < .02). CONCLUSIONS: Myocardial ischemia was evident in a high proportion (one third) of the patients after surgery. A pragmatic regimen of perioperative beta-blockade with metoprolol did not seem to reduce 30-day cardiovascular events, but it did decrease the time from surgery to discharge.     

Relationship between β1‐adrenergic receptor polymorphisms and cardiovascular disease in patients with diabetic nephropathy

Aim: Activation of β1‐adrenergic receptor (β1AR) enhances contractility and heart rate. The polymorphism Arg389Gly in the β1AR gene was found to be functionally important in determining receptor activity. The relationship between this polymorphism and the risk of cardiovascular disease was investigated in Chinese subjects with overt diabetic nephropathy. Methods: A total of 219 type 2 diabetic subjects with nephropathy were recruited. Genotyping of the β1AR Arg389Gly polymorphism was determined. Patients were followed up to 96 months for the development of cardiovascular events. Results: There were 122, 86 and 11 patients with Arg/Arg, Arg/Gly and Gly/Gly genotype, respectively. At 96 months, the event‐free survival of primary composite cardiovascular end‐point was 33.0% and 44.3% for Gly⁺ and Gly^‐ groups, respectively (log–rank test, P = 0.105), while the event‐free survival for first ischaemic heart disease was 62.4% and 75.9%, respectively (log–rank test, P = 0.038). However, with multivariate analysis by the Cox proportional hazard model to adjust for confounders, only low‐density lipoprotein and baseline glomerular filtration rate were independent predictors of first ischaemic heart event. Conclusion: The β1AR Arg389Gly polymorphism is not an independent predictor of cardiovascular events in subjects with overt diabetic nephropathy.     

The timing of intravenous crystalloid administration and incidence of cardiovascular side effects during spinal anesthesia: the results from a randomized controlled trial.

We conducted a randomized clinical trial to evaluate the efficacy of crystalloids in preventing spinal-induced hypotension (SIH) and cardiovascular side effects (CVSE) in a group of surgical patients. Participants were assigned to receive lactated Ringer's solution at 1-2 mL/min (Placebo group, n = 142); lactated Ringer's at 20 mL/kg starting 20 min before spinal block (n = 130); or lactated Ringer's at 20 mL/kg starting at the time of spinal block (n = 132). SIH was defined as a decrease of > or = 30% in baseline systolic blood pressure, and CVSE as SIH plus nausea, vomiting, or faintness requiring treatment. The incidence of SIH was similar in all treatment groups. Compared to placebo, crystalloid administration at the time of spinal block resulted in a significant reduction in the proportion of patients developing CVSE from 9.9% to 2.3%. The corresponding relative proportion was 0.23 (95% confidence interval, 0.07-0.78; P = 0.019), and one additional case of CVSE was avoided for each 13 patients receiving crystalloids at the time of spinal block instead of placebo. Administration of crystalloids at the time of spinal block seems to be effective because it provides additional intravascular fluids during the period of highest risk of CVSE after spinal anesthesia. IMPLICATIONS: Crystalloids are frequently administered to nonobstetric patients minutes before spinal anesthesia to prevent cardiovascular side effects (CVSE). This randomized controlled trial shows that although crystalloids administered before spinal block result in no clinical benefit, they significantly reduce the risk of CVSE when administered at the time of spinal block.     

Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease--results of the renal Hope-2 study.

BACKGROUND: Elevated plasma homocysteine levels are reported to be associated with higher rates of vascular diseases. Plasma homocysteine increases in chronic kidney disease (CKD) and could contribute to the increased cardiovascular risk in CKD. METHODS: Participants aged 55 years or older with CKD, defined as estimated GFR<60 ml/min and at high cardiovascular risk, were randomly assigned to the combination of folic acid, 2.5 mg, vitamin B6, 50 mg and vitamin B12, 1 mg (n = 307) or placebo (n = 312) daily for 5 years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction and stroke. RESULTS: Mean baseline plasma homocysteine was 15.9 +/- 7.3 micromol/l in the active treatment group and 15.7 +/- 5.7 micromol/l in placebo group and decreased to 11.9 +/- 3.3 micromol/l (P < 0.001) on active treatment (15.5 +/- 4.5 on placebo). Primary outcome events occurred in 90 participants (29.3%) on active therapy and in 80 (25.6%) on placebo (relative risk, 1.19; 95% confidence interval, 0.88-1.61; P = 0.25). There were no significant treatment benefits on death from cardiovascular causes (1.24; 0.84-1.83), myocardial infarction (1.10; 0.76-1.61) and stroke (1.00; 0.54-1.85). More participants in the active treatment group were hospitalized for heart failure (1.98; 1.21-3.26; P = 0.007) and for unstable angina (1.70; 1.02-2.83; P = 0.04). Incidence of primary outcome increased with decreasing GFR. CONCLUSIONS: Active treatment with B vitamins lowered homocysteine levels in participants with CKD but did not reduce cardiovascular risk.     

CAGS and ACS Evidence Based Reviews in Surgery. 34: Effects of β-blockers in patients undergoing noncardiac surgery

Question: Do β-blockers have an effect on the 30-day risk of major cardiovascular events in patients with or at risk of atherosclerotic disease undergoing noncardiac surgery? Design: Randomized controlled trial. Setting: Multicentre trial in 190 hospitals in 23 countries. Patients: In total, 8351 patients with or at risk of atherosclerotic disease undergoing noncardiac surgery. Intervention: Patients were randomly assigned by a computerized 24-hour phone service to receive extended-release metoprolol succinate 200 mg (n = 4174) or placebo (n = 4177). Treatment was started 2–4 hours before surgery and continued for 30 days. Main outcome: Cardiovascular death, nonfatal myocardial infarction (MI) and nonfatal cardiac arrest. Results: Of those randomized, 8331 (99.8%) patients completed the 30-day follow-up. Fewer patients in the metoprolol group than in the placebo group had an MI (176 [4.2%] v. 239 [5.7%] patients; hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.60–0.089, p = 0.0017). However, there were more deaths in the metoprolol group than in the placebo group (129 [3.1%] v. 97 [2.3%] patients; HR 1.33, 95% CI 1.03–1.74, p = 0.0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1.0%] v. 19 [0.5%] patients; HR 2.17, 95% CI 1.26–3.74, p = 0.0053). Conclusion: A perioperative β-blocker regimen results in fewer MIs but is associated with an increased risk of stroke and perioperative death in patients with or at risk for atherosclerotic disease undergoing noncardiac surgery. Patients are unlikely to accept the risks associated with perioperative extended-release metoprolol use.     

The ILAILL study: iloprost as adjuvant to surgery for acute ischemia of lower limbs: a randomized, placebo-controlled, double-blind study by the italian society for vascular and endovascular surgery

SUMMARY BACKGROUND DATA: High rate of complications has been reported following revascularization for acute limb ischemia (ALI). No adjuvant pharmacologic treatment, apart from anticoagulation and standard perioperative care, has been shown clinically effective. OBJECTIVE: Aim of this study was to evaluate the effects of the prostacyclin analog iloprost as adjuvant to surgery for ALI. METHODS: A total of 300 patients were randomly assigned to receive perioperative iloprost (intra-arterial, intraoperative bolus of 3000 ng, plus intravenous infusion of 0.5-2.0 ng/kg/min for 6 hours/day for 4-7 days following surgery), or placebo. The primary endpoint was the combined incidence of death and amputation at 3-month follow-up. Secondary endpoints were the incidence of each single major complication, total event rate, symptomatology, and tolerability. RESULTS: The combined incidence of death and amputation was 19.9% in the placebo and 14.1% in the iloprost group (relative risk, 1.56; 95% confidence interval, 0.89-2.75, P = 0.12, Cox regression analysis). A statistically significant lower mortality (4.7%) was reported in patients receiving iloprost, compared with controls (10.6%; relative risk, 2.61; 95% confidence interval, 1.07-6.37, P = 0.03). The overall incidence of fatal plus major cardiovascular events was 33.1% and 22.8% in placebo and iloprost groups, respectively (relative risk, 1.61; 95% confidence interval, 1.04-2.49, P = 0.03). No serious adverse reactions occurred after iloprost administration, nor differences in the incidence of bleeding or hypotension between treatment groups. CONCLUSIONS: Although at lower levels than previously reported, our results confirm the severity of ALI. Iloprost as adjuvant to surgery significantly reduced mortality and overall major event rate. Further data are needed to support this finding, and to face a still open medical issue.     

Increase in creatinine and cardiovascular risk in patients with systolic dysfunction after myocardial infarction

Baseline renal function is a potent independent risk factor for adverse events after acute myocardial infarction (MI). Worsening renal function (WRF) has been shown to influence outcomes in the heart failure population, but its impact on cardiovascular risk in the post-MI period has not been well defined. For assessment of the prognostic importance of WRF, 2231 patients who had left ventricular dysfunction and were enrolled in the Survival and Ventricular Enlargement (SAVE) trial were studied. Patients were randomly assigned between 3 and 16 d (average 11 d) after acute MI to receive captopril or placebo; those with a serum creatinine of >2.5 mg/dl were excluded from SAVE. WRF was defined as an increase in creatinine of >0.3 mg/dl measured from baseline to 2 wk after randomization. The predictive value of WRF on cardiovascular morbidity and mortality was examined during 42 mo of follow-up. Paired serum creatinine measurements at baseline and 2 wk were available in 1854 patients. WRF occurred in 223 (12.0%) patients and was a stronger predictor of death (hazard ratio [HR] 1.46; 95% confidence interval [CI] 1.05 to 2.02) than baseline creatinine (HR 1.31; 95% CI 1.01 to 1.70). WRF also showed an increased risk for cardiovascular death (HR 1.62; 95% CI 1.14 to 2.30) and the composite end point (HR 1.32; 95% CI 1.03 to 1.70). When stratified by treatment, 104 (5.7%) and 116 (6.4%) patients with WRF in the placebo and captopril groups had no significant association between treatment group and WRF (P = 0.38). The risk for death associated with WRF was HR 1.63 (95% CI 1.05 to 2.52) in the placebo group compared with HR 1.33 (95% CI 0.81 to 2.21) in the captopril group (P = 0.49 for interaction). WRF as early as 2 wk after MI was not uncommon (12.0%) and was associated with increased mortality in patients without renal dysfunction at baseline. Patients who received captopril did not demonstrate more WRF than patients who received placebo. Monitoring serum creatinine in patients during the first few weeks after MI may help to identify those who are at highest risk and guide effective long-term therapeutic choices.     

Renal insufficiency and mortality in patients with known or suspected coronary artery disease

It remains unclear whether mild renal dysfunction is associated with adverse cardiovascular outcome. We investigated whether estimated glomerular filtration rate (eGFR) was associated with mortality and cardiac death among 6447 patients with known or suspected coronary artery disease over a mean follow-up of 7 yr. Cumulative 5- and 10-yr survival rates decreased in a graded fashion from 88% and 70%, respectively, for those with normal renal function to 43% and 33% for those with eGFR <30 ml/min. Compared with patients with normal renal function, the multivariable adjusted hazard ratios for all-cause mortality among patients with mild, moderate, and severe renal impairment were 1.33 (95% confidence interval [CI], 1.21-1.48), 1.67 (95% CI, 1.44-1.93), and 3.38 (95% CI, 2.73-4.19), respectively. Similar relationships between cardiac death and decreasing renal function were found. In conclusion, renal function is a graded and independent predictor of long-term mortality in patients with known or suspected coronary artery disease. Intense treatment and close surveillance of these patients is encouraged.     

Cardiovascular disease and hypertension risk in living kidney donors: an analysis of health administrative data in Ontario, Canada

BACKGROUND: Knowledge of any harm associated with living kidney donation guides informed consent and living donor follow-up. Risk estimates in the literature are variable, and most studies did not use a healthy control group to assess outcomes attributable to donation. METHODS: We observed a retrospective cohort using health administrative data for donations which occurred in Ontario, Canada between the years 1993 and 2005. There were a total of 1278 living donors and 6359 healthy adults who acted as a control group. Individuals were followed for a mean of 6.2 years (range, 1-13 years) after donation. The primary outcome was a composite of time to death or first cardiovascular event (myocardial infarction, stroke, angioplasty, and bypass surgery). The secondary outcome was time to a diagnosis of hypertension. RESULTS: There was no significant difference in death or cardiovascular events between donors and controls (1.3% vs. 1.7%; hazard ratio 0.7, 95% confidence interval 0.4-1.2). Donors were more frequently diagnosed with hypertension than controls (16.3% vs. 11.9%, hazard ratio 1.4, 95% confidence interval 1.2-1.7) but were also seen more often by their primary care physicians (median [interquartile range] 3.6 [1.9-6.1] vs. 2.6 [1.4-4.3] visits per person year, P<0.001). CONCLUSIONS: Based on administrative data, the risk of cardiovascular disease was unchanged in the first decade after kidney donation. The observed increase in diagnosed hypertension may be due to nephrectomy or more blood pressure measurements received by donors in follow-up and requires prospective study.     

Efficacy and safety of itraconazole prophylaxis for fungal infections after orthotopic liver transplantation: a prospective, randomized, double-blind study

BACKGROUND: There is significant morbidity and mortality related to fungal infections in the solid-organ transplant population. METHODS: A prospective, randomized, double-blind, placebo-controlled, restricted sequential design trial was performed in 71 adults undergoing orthotopic liver transplantation. Patients were randomly assigned to receive either itraconazole (5.0 mg/kg orally, preoperatively, 2.5 mg/kg orally, two times a day, postoperatively) or placebo. Therapy continued for a maximum of 56 days or until patient was discharged from hospital or met a predefined endpoint. Measurements included incidence of fungal colonization, superficial or systemic fungal infections requiring systemic therapy, adverse events, and mortality rate. RESULTS: This trial design supported the superiority of itraconazole in preventing fungal infections; nine patients in the placebo group (24%; 95% confidence interval, 0.118-0.412) and one patient in the itraconazole group (4%; 95% confidence interval, 0.001-0.204) developed fungal endpoints requiring therapy with amphotericin B (P=0.04, Fisher's exact test). At the time of enrollment, fungal colonization occurred in 40% and 37% of itraconazole and placebo patients (P=0.43), respectively. Adverse events were reported by 97% and 100% of the intraconazole and placebo groups, respectively, and one itraconazole and six placebo-group patients died within the study period. There was no relation to trial medication for serious adverse events. CONCLUSION: Prophylaxis with itraconazole reduces fungal infections in patients undergoing orthotopic liver transplantation and is well tolerated.     

Effect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes

In patients with ESRD, the effects of online hemodiafiltration on all-cause mortality and cardiovascular events are unclear. In this prospective study, we randomly assigned 714 chronic hemodialysis patients to online postdilution hemodiafiltration (n=358) or to continue low-flux hemodialysis (n=356). The primary outcome measure was all-cause mortality. The main secondary endpoint was a composite of major cardiovascular events, including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, therapeutic coronary intervention, therapeutic carotid intervention, vascular intervention, or amputation. After a mean 3.0 years of follow-up (range, 0.4-6.6 years), we did not detect a significant difference between treatment groups with regard to all-cause mortality (121 versus 127 deaths per 1000 person-years in the online hemodiafiltration and low-flux hemodialysis groups, respectively; hazard ratio, 0.95; 95% confidence interval, 0.75-1.20). The incidences of cardiovascular events were 127 and 116 per 1000 person-years, respectively (hazard ratio, 1.07; 95% confidence interval, 0.83-1.39). Receiving high-volume hemodiafiltration during the trial associated with lower all-cause mortality, a finding that persisted after adjusting for potential confounders and dialysis facility. In conclusion, this trial did not detect a beneficial effect of hemodiafiltration on all-cause mortality and cardiovascular events compared with low-flux hemodialysis. On-treatment analysis suggests the possibility of a survival benefit among patients who receive high-volume hemodiafiltration, although this subgroup finding requires confirmation.     

Impact of Heart Failure on Patients Undergoing Major Noncardiac Surgery

Background: Changes in the demographics and epidemiology of patients with cardiovascular comorbidities who undergo major noncardiac surgery require an updated assessment of which patients are at greater risk of mortality or readmission. The authors evaluated short-term outcomes among patients with heart failure, coronary artery disease (CAD), or neither who underwent major noncardiac surgery.

Methods: Patients were aged 65 and older, had Medicare fee-for-service coverage, and underwent 1 of 13 major noncardiac procedures from 2000 through 2004, excluding patients with end-stage renal disease and patients who did not have at least 1 yr of Medicare fee-for-service eligibility before surgery. Main outcome measures were operative mortality and 30-day all-cause readmission.

Results: Of 159,327 procedures, 18% were performed in patients with heart failure and 34% were performed in patients with CAD. Adjusted hazard ratios of mortality and readmission for patients with heart failure, compared with patients with neither heart failure nor CAD, were 1.63 (95% confidence interval, 1.52-1.74) and 1.51 (95% confidence interval, 1.45-1.58), respectively. Adjusted hazard ratios of mortality and readmission for patients with CAD, compared with patients with neither heart failure nor CAD, were 1.08 (95% confidence interval, 1.01-1.16) and 1.16 (95% confidence interval, 1.12-1.20), respectively. These effects were statistically significant. Patients with heart failure were at significantly higher risk for both outcomes compared with patients with CAD.     

Activated injectable vitamin D and hemodialysis survival: a historical cohort study

Patients with ESRD commonly experience secondary hyperparathyroidism, a condition primarily managed with activated injectable vitamin D. The biologic effects of vitamin D, however, are widespread, and it is possible that activated injectable vitamin D alters survival in ESRD. This hypothesis was tested in a historical cohort study of incident hemodialysis patients who lived throughout the United States between January 1996 and December 1999. The primary outcome was 2-yr survival among those who survived for at least 90 d after initiation of chronic hemodialysis. During this period, 51,037 chronic hemodialysis patients survived for at least 90 d from the initiation of hemodialysis, and in the ensuing 2 yr, 37,173 received activated injectable vitamin D and 13,864 did not. At 2 yr, mortality rates were 13.8/100 person-years in the group that received injectable vitamin D compared with 28.6/100 person-years in the group that did not (P < 0.001). Cox proportional hazards analyses adjusting for several potential confounders and examining injectable vitamin D therapy as a time-dependent exposure suggested that compared with patients who did not receive injectable vitamin D, the 2-yr survival advantage associated with the group that did receive injectable vitamin D was 20% (hazard ratio, 0.80; 95% confidence interval, 0.76 to 0.83). The incidence of cardiovascular-related mortality was 7.6/100 person-years in the injectable vitamin D group, compared with 14.6/100 person-years in the non-vitamin D group (P < 0.001). The benefit of injectable vitamin D was evident in 48 of 49 strata examined, including those with low serum levels of intact parathyroid hormone and elevated levels of serum calcium and phosphorus, situations in which injectable vitamin D is often withheld. Repeating the entire analysis using marginal structural models to adjust for time-dependent confounding by indication yielded a survival advantage of 26% (hazard ratio, 0.74; 95% confidence interval, 0.71 to 0.79) associated with the injectable vitamin D group. In this historical cohort study, chronic hemodialysis patients in the group that received injectable vitamin D had a significant survival advantage over patients who did not. Randomized clinical trials would permit definitive conclusions.     

N-Terminal Pro-brain Natriuretic Peptide Identifies Patients at High Risk for Adverse Cardiac Outcome after Vascular Surgery

Background: Preoperative N-terminal pro-BNP (NT-proBNP) is independently associated with adverse cardiac outcome but does not anticipate the dynamic consequences of anesthesia and surgery. The authors hypothesized that a single postoperative NT-proBNP level provides additional prognostic information for in-hospital and late cardiac events.

Methods: Two hundred eighteen patients scheduled to undergo vascular surgery were enrolled and followed up for 24-30 months. Logistic regression and Cox proportional hazards model were performed to evaluate predictors of in-hospital and long-term cardiac outcome. The optimal discriminatory level of preoperative and postoperative NT-proBNP was determined by receiver operating characteristic analysis.

Results: During a median follow-up of 826 days, 44 patients (20%) experienced 51 cardiac events. Perioperatively, median NT-proBNP increased from 215 to 557 pg/ml (interquartile range, 83/457 to 221/1178 pg/ml; P < 0.001). The optimum discriminate threshold for preoperative and postoperative NT-proBNP was 280 pg/ml (95% confidence interval, 123-400) and 860 pg/ml (95% confidence interval, 556-1,054), respectively. Adjusted for age, previous myocardial infarction, preoperative fibrinogen, creatinine, high-sensitivity C-reactive protein, type, duration, and surgical complications, only postoperative NT-proBNP remained significantly associated with in-hospital (adjusted hazard ratio, 19.8; 95% confidence interval, 3.4-115) and long-term cardiac outcome (adjusted hazard ratio, 4.88; 95% confidence interval, 2.43-9.81).     

Perioperative granulocyte colony-stimulating factor does not prevent severe infections in patients undergoing esophagectomy for esophageal cancer: a randomized placebo-controlled clinical trial

OBJECTIVE: Esophagectomy for esophageal cancer is associated with substantial postoperative morbidity as a result of infectious complications. In a prior phase II study, granulocyte colony-stimulating factor (G-CSF) was shown to improve leukocyte function and to reduce infection rates after esophagectomy. The aim of the current randomized, placebo-controlled, multicenter phase III trial was to investigate the clinical efficacy of perioperative G-CSF administration in reducing infection and mortality after esophagectomy for esophageal cancer. PATIENTS AND METHODS: One hundred fifty five patients with resectable esophageal cancer were randomly assigned to perioperative G-CSF at standard doses (77 patients) or placebo (76 patients), administered from 2 days before until day 7 after esophagectomy. The G-CSF and placebo groups were comparable as regards age, gender, risk, cancer stage, frequency of neoadjuvant radiochemotherapy, and type of esophagectomy (transthoracic or transhiatal esophageal resection). RESULTS: Of 155 randomized patients, 153 were eligible for the intention-to-treat analysis. The rate of infection occurring within the first 10 days after esophagectomy was 43.4% (confidence interval 32.8-55.9%) in the placebo and 44.2% (confidence interval 32.1-55.3%) in the G-CSF group (P = 0.927). 30-day mortality amounted to 5.2% in the G-CSF group versus 5.3% in the placebo group (P = 0.985). Similar results were found in the per-protocol analysis. CONCLUSION: Perioperative administration of G-CSF failed to reduce postoperative morbidity, infection rate, or mortality in patients with esophageal cancer who underwent esophagectomy.     

Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A Study in Long-term Effects)

BACKGROUND: Cilostazol, a phosphodiesterase III inhibitor, is indicated to treat the symptoms of intermittent claudication and increase walking distance in patients with peripheral arterial disease (PAD). At the time of approval, the United States Food and Drug Administration required an additional long-term safety study to evaluate the effect cilostazol on mortality. METHODS: A total of 1899 subjects with a clinical diagnosis of PAD and symptoms of claudication were screened for participation in a randomized, double-blinded, placebo-controlled safety study of cilostazol. The intent-to-treat (ITT) population, which was the primary analysis (n = 1435), was defined as all randomized patients who received at least one dose of study medication and included patients who were followed up >30 days after discontinuation of study drug. A total of 717 patients received cilostazol and 718 received placebo. Cilostazol was administered at a primary dose of 100 mg twice daily. The dose could be reduced to 50 mg twice daily if patients experienced an adverse event that might have been drug related. RESULTS: Long-term adherence to study medication was poor, with >60% of participants discontinuing therapy by 36 months. The mortality analysis therefore focused on deaths during the period on-treatment, defined as the period during which the study drug was taken plus a 30-day follow-up period after dosing. Total patient-years of exposure were 1046 on-treatment for cilostazol and 1090 for placebo. On-treatment, there were 18 deaths on cilostazol and 19 deaths on placebo for a hazard ratio of 0.99 (95% confidence interval [CI], 0.52-1.88). Cardiovascular deaths on-treatment occurred in 14 patients on cilostazol and 14 on placebo. In the full ITT population at 36 months, there were 101 deaths, 49 on cilostazol and 52 on placebo, with hazard ratio of 0.94 (95% CI, 0.64-1.39). Thus, most deaths occurred >30 days after study drug discontinuation. Serious bleeding events affected 18 patients taking cilostazol in the on-treatment population and 22 taking placebo. The rates of bleeding events were similar in patients who used aspirin, aspirin plus clopidogrel, or anticoagulants at anytime during the course of the study CONCLUSIONS: This long-term study demonstrated no safety signal for cilostazol on all-cause or cardiovascular mortality. The study, however, was underpowered to detect a small adverse impact of cilostazol on mortality (hazard ratio upper bound of the 95% CI was 1.88 in the on-treatment population). Serious bleeding events appeared not to be increased by cilostazol.     

Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial

OBJECTIVES: This prospective, randomized, placebo-controlled, double-blind clinical trial was performed to analyze the effect of atorvastatin compared with placebo on the occurrence of a 6-month composite of cardiovascular events after vascular surgery. Cardiovascular complications are the most important cause of perioperative morbidity and mortality among patients undergoing vascular surgery. Statin therapy may reduce perioperative cardiac events through stabilization of coronary plaques. METHODS: One hundred patients were randomly assigned to receive 20 mg atorvastatin or placebo once a day for 45 days, irrespective of their serum cholesterol concentration. Vascular surgery was performed on average 30 days after randomization, and patients were prospectively followed up over 6 months. The cardiovascular events studied were death from cardiac cause, nonfatal myocardial infarction, unstable angina, and stroke. RESULTS: Fifty patients received atorvastatin, and 50 received placebo. During the 6-month follow-up primary end points occurred in 17 patients, 4 in the atorvastatin group and 13 in the placebo group. The incidence of cardiac events was more than three times higher with placebo (26.0%) compared with atorvastatin (8.0%; P =.031). The risk for an event was compared between the groups with the Kaplan-Meier method, as event-free survival after vascular surgery. Patients given atorvastatin exhibited a significant decrease in the rate of cardiac events, compared with the placebo group, within 6 months after vascular surgery (P =.018). CONCLUSION: Short-term treatment with atorvastatin significantly reduces the incidence of major adverse cardiovascular events after vascular surgery.     

Comparison of Morphine, Ketorolac, and Their Combination for Postoperative Pain: Results from a Large, Randomized, Double-blind Trial

Background: Meta-analyses report similar numbers needed to treat for nonsteroidal antiinflammatory drugs (NSAIDs) and opioids. Differences in baseline pain intensity among the studies from which these numbers needed to treat were derived may have confounded the results. NSAIDs have an opioid-sparing effect, but the importance of this effect is unclear. Therefore, the authors sought to compare the proportions of subjects who obtain pain relief with ketorolac versus morphine after surgery and to determine whether the opioid-sparing effect of an NSAID reduces the magnitude of opioid side effects.

Methods: The study was a double-blind, randomized controlled trial. The authors randomly assigned 1,003 adult patients to receive 30 mg ketorolac or 0.1 mg/kg morphine intravenously. They calculated the proportion of subjects who achieved at least 50% reduction in pain intensity 30 min after analgesic administration. Further, so long as pain intensity 30 min after analgesic administration was 5 or more out of 10, patients received 2.5 mg morphine every 10 min until pain intensity was 4 or less out of 10. The authors assessed the presence of opioid-related side effects.

Results: Five hundred patients received morphine and 503 received ketorolac. Fifty percent of patients in the morphine group achieved pain relief, compared with 31% in the ketorolac group (difference, 19%; 95% confidence interval, 13-25%). The ketorolac-morphine group required less morphine (difference, 6.5 mg; 95% confidence interval, -5.8 to -7.2) and had a lower incidence of side effects (difference, 11%; 95% confidence interval, 5-16%) than the morphine group.