Franz Wiesbauer

Perioperative -Blockers for Preventing Surgery-Related Mortality and Morbidity: A Systematic Review and Meta-Analysis

BACKGROUND:Perioperative &bgr;-blockers are suggested to reduce cardiovascular mortality, myocardial–ischemia/infarction, and supraventricular arrhythmias after surgery. We reviewed the evidence regarding the effectiveness of perioperative &bgr;-blockers for improving patient outcomes after cardiac and noncardiac surgery. METHODS:Eleven large databases were searched from the time of their inception until October 2005. Various online-resources were consulted for the identification of unpublished trials and conference abstracts. We included randomized, controlled trials comparing perioperative &bgr;-blockers with either placebo or the standard-of-care. Of the 3680 retrieved titles, 69 met inclusion criteria for analysis. Odds ratios (OR) assuming random effects were computed in the absence of significant clinical heterogeneity. RESULTS:&bgr;-Blockers reduced the frequency of ventricular tachyarrhythmias [OR (cardiac surgery): 0.28, 95% CI 0.13–0.57; OR (noncardiac surgery): 0.56, 95% CI 0.21–1.45], atrial fibrillation/flutter [OR (cardiac surgery): 0.37, 95% CI 0.28–0.48], other supraventricular arrhythmias [OR (cardiac surgery): 0.25, 95% CI 0.18–0.35; OR (noncardiac surgery): 0.43, 95% CI 0.14–1.37], and myocardial ischemia [OR (cardiac surgery): 0.49, 95% CI 0.17–1.4; OR (noncardiac surgery): 0.38, 95% CI 0.21–0.69]. Length of hospitalization was not reduced [weighted mean difference (cardiac surgery): −0.35 days, 95% CI −0.77–0.07; weighted mean difference (noncardiac surgery): −5.59 days, 95% CI −12.22–1.04] and, in contrast to previous reports, &bgr;-blockers did not reduce mortality [OR (cardiac surgery): 0.55, 95% CI 0.17–1.83; OR (noncardiac surgery): 0.78, 95% CI 0.33–1.87], and they had no influence on the occurrence of perioperative myocardial infarction [OR (cardiac surgery): 0.89, 95% CI 0.53–1.5; OR (noncardiac surgery): 0.59; 0.25–1.39]. CONCLUSIONS:&bgr;-Blockers reduced perioperative arrhythmias and myocardial ischemia, but they had no effect on myocardial infarction, mortality, or length of hospitalization.

Familial-combined hyperlipidaemia in very young myocardial infarction survivors (≤40 years of age)

AIMSnMyocardial infarction (MI) in very young individuals is a rare disease associated with an unfavourable prognosis. Familial-combined hyperlipidaemia (FCHL) increases the risk for MI in individuals below 60 years; however, its role in very young MI patients below 40 years is not as well established. We investigated the prevalence and impact of FCHL in these very young MI patients.nnnMETHODS AND RESULTSnWe prospectively enrolled 102 consecutive MI survivors (< or =40 years) from two high-volume cardiac catheterization centres. Patients were frequency-matched for age, gender, and centre to 200 hospital controls free from coronary heart disease. Myocardial infarction patients were invited to send family members for FCHL screening. Overall, 37 families were screened. Familial-combined hyperlipidaemia was diagnosed using a nomogram, which takes into account total cholesterol, triglycerides, and Apo B(100) levels. Thirty-eight acute myocardial infarction (AMI) patients (38%) and five controls (2.5%) displayed the FCHL phenotype, 21 of these MI patients sent family members for screening, and FCHL was confirmed in 16 families (76%). The FCHL phenotype was associated with a 24-fold increased adjusted risk for MI (95% CI 7.5-81, P < 0.001). Of all lipid parameters, VLDL-cholesterol, and non-HDL-cholesterol were most strongly associated with MI.nnnCONCLUSIONSnThe present study suggests that the FCHL phenotype seems to be a major risk factor for the occurrence of MI at a very young age. It remains to be determined whether this excessively increased risk can be favourably modified by therapeutic interventions.

Statin Use Is Associated with Prolonged Survival of Renal Transplant Recipients

The efficacy of statins for the prevention of cardiovascular events is well established in the general population but remains unknown in renal transplant recipients. In this study, the association of statin use with patient and graft survival was investigated in a cohort of 2041 first-time recipients of renal allografts between 1990 and 2003. Multivariable Cox regression demonstrated that statin use was independently associated with lower mortality rates. Twelve-year survival rates were 73% for statin users and 64% for nonusers (P = 0.055). The adjusted hazard ratio for all-cause mortality associated with statin use was 0.64 (95% confidence interval 0.48 to 0.86). Graft survival rates during the same time period were 76% for statin users and 70% for nonusers (P = 0.055). The adjusted hazard ratio for graft survival associated with statin use was 0.76 (95% confidence interval 0.55 to 1.04). Results from marginal structural models were virtually identical. In summary, statin use was associated with prolonged patient survival, but no difference in graft survival was detected. Although these results are encouraging, a definitive causal relationship can be determined only from randomized clinical trials.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity.

BACKGROUNDnRandomized controlled trials have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue.nnnOBJECTIVESnThe objective of this review was to systematically analyse the effects of perioperatively administered beta-blockers for prevention of surgery-related mortality and morbidity in patients undergoing any type of surgery while under general anaesthesia.nnnSEARCH METHODSnWe identified trials by searching the following databases from the date of their inception until June 2013: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Biosis Previews, CAB Abstracts, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Derwent Drug File, Science Citation Index Expanded, Life Sciences Collection, Global Health and PASCAL. In addition, we searched online resources to identify grey literature.nnnSELECTION CRITERIAnWe included randomized controlled trials if participants were randomly assigned to a beta-blocker group or a control group (standard care or placebo). Surgery (any type) had to be performed with all or at least a significant proportion of participants under general anaesthesia.nnnDATA COLLECTION AND ANALYSISnTwo review authors independently extracted data from all studies. In cases of disagreement, we reassessed the respective studies to reach consensus. We computed summary estimates in the absence of significant clinical heterogeneity. Risk ratios (RRs) were used for dichotomous outcomes, and mean differences (MDs) were used for continuous outcomes. We performed subgroup analyses for various potential effect modifiers.nnnMAIN RESULTSnWe included 89 randomized controlled trials with 19,211 participants. Six studies (7%) met the highest methodological quality criteria (studies with overall low risk of bias: adequate sequence generation, adequate allocation concealment, double/triple-blinded design with a placebo group, intention-to-treat analysis), whereas in the remaining trials, some form of bias was present or could not be definitively excluded (studies with overall unclear or high risk of bias). Outcomes were evaluated separately for cardiac and non-cardiac surgery. CARDIAC SURGERY (53 trials)We found no clear evidence of an effect of beta-blockers on the following outcomes.• All-cause mortality: RR 0.73, 95% CI 0.35 to 1.52, 3783 participants, moderate quality of evidence.• Acute myocardial infarction (AMI): RR 1.04, 95% CI 0.71 to 1.51, 3553 participants, moderate quality of evidence.• Myocardial ischaemia: RR 0.51, 95% CI 0.25 to 1.05, 166 participants, low quality of evidence.• Cerebrovascular events: RR 1.52, 95% CI 0.58 to 4.02, 1400 participants, low quality of evidence.• Hypotension: RR 1.54, 95% CI 0.67 to 3.51, 558 participants, low quality of evidence.• Bradycardia: RR 1.61, 95% CI 0.97 to 2.66, 660 participants, low quality of evidence.• Congestive heart failure: RR 0.22, 95% CI 0.04 to 1.34, 311 participants, low quality of evidence.Beta-blockers significantly reduced the occurrence of the following endpoints.• Ventricular arrhythmias: RR 0.37, 95% CI 0.24 to 0.58, number needed to treat for an additional beneficial outcome (NNTB) 29, 2292 participants, moderate quality of evidence.• Supraventricular arrhythmias: RR 0.44, 95% CI 0.36 to 0.53, NNTB six, 6420 participants, high quality of evidence.• On average, beta-blockers reduced length of hospital stay by 0.54 days (95% CI -0.90 to -0.19, 2450 participants, low quality of evidence). NON-CARDIAC SURGERY (36 trials)We found a potential increase in the occurrence of the following outcomes with the use of beta-blockers.• All-cause mortality: RR 1.24, 95% CI 0.99 to 1.54, 11,463 participants, low quality of evidence.Whereas no clear evidence of an effect was noted when all studies were analysed, restricting the meta-analysis to low risk of bias studies revealed a significant increase in all-cause mortality with the use of beta-blockers: RR 1.27, 95% CI 1.01 to 1.59, number needed to treat for an additional harmful outcome (NNTH) 189, 10,845 participants.• Cerebrovascular events: RR 1.59, 95% CI 0.93 to 2.71, 9150 participants, low quality of evidence.Whereas no clear evidence of an effect was found when all studies were analysed, restricting the meta-analysis to low risk of bias studies revealed a significant increase in cerebrovascular events with the use of beta-blockers: RR 2.09, 95% CI 1.14 to 3.82, NNTH 255, 8648 participants.Beta-blockers significantly reduced the occurrence of the following endpoints.• AMI: RR 0.73, 95% CI 0.61 to 0.87, NNTB 72, 10,958 participants, high quality of evidence.• Myocardial ischaemia: RR 0.43, 95% CI 0.27 to 0.70, NNTB seven, 1028 participants, moderate quality of evidence.• Supraventricular arrhythmias: RR 0.72, 95% CI 0.56 to 0.92, NNTB 111, 8794 participants, high quality of evidence.Beta-blockers significantly increased the occurrence of the following adverse events.• Hypotension: RR 1.50, 95% CI 1.38 to 1.64, NNTH 15, 10,947 participants, high quality of evidence.• Bradycardia: RR 2.24, 95% CI 1.49 to 3.35, NNTH 18, 11,083 participants, moderate quality of evidence.We found no clear evidence of an effect of beta-blockers on the following outcomes.• Ventricular arrhythmias: RR 0.64, 95% CI 0.30 to 1.33, 526 participants, moderate quality of evidence.• Congestive heart failure: RR 1.17, 95% CI 0.93 to 1.47, 9223 participants, moderate quality of evidence.• Length of hospital stay: mean difference -0.27 days, 95% CI -1.29 to 0.75, 601 participants, low quality of evidence.nnnAUTHORS CONCLUSIONSnAccording to our findings, perioperative application of beta-blockers still plays a pivotal role in cardiac surgery , as they can substantially reduce the high burden of supraventricular and ventricular arrhythmias in the aftermath of surgery. Their influence on mortality, AMI, stroke, congestive heart failure, hypotension and bradycardia in this setting remains unclear.In non-cardiac surgery, evidence from low risk of bias trials shows an increase in all-cause mortality and stroke with the use of beta-blockers. As the quality of evidence is still low to moderate, more evidence is needed before a definitive conclusion can be drawn. The substantial reduction in supraventricular arrhythmias and AMI in this setting seems to be offset by the potential increase in mortality and stroke.

Relative importance of different lipid risk factors for the development of myocardial infarction at a very young age (≤ 40 years of age)

Eur J Clin Invest 2012; 42 (6): 631–636

Glucose control is associated with patient survival in diabetic patients after renal transplantation.

Introduction. The efficacy of tight glycemic control for the prevention of death and renal failure in the general diabetic population is well established. However, in diabetic renal-allograft recipients, the effect of different treatment strategies on outcomes is undetermined. Methods. We conducted a cohort study of 798 diabetic, renal-allograft recipients transplanted at the Medical University of Vienna between 1990 and 2004. We studied the influence of glucose parameters and diabetes treatment on mortality and graft loss. Marginal-structural models and multivariable Cox regression analysis were used to control for confounding. Results. Maximal glucose levels but not HbA1c were independently associated with mortality. Being in the highest quartile of maximal glucose increased the adjusted risk of death by a factor of 2.2 (P value for trend 0.009). Furthermore, in patients receiving insulin, the risk of death was increased 1.7-fold (95% confidence interval 0.9–3.1) compared with diet and 2.0-fold (95% confidence interval 1.1–3.7) compared with oral medication. Maximal glucose, HbA1c, or diabetes treatment did not influence death-censored functional graft survival. Discussion. In conclusion, maximal glucose levels and insulin treatment were independently associated with higher rates of mortality in our cohort of diabetic, renal-allograft recipients. However, graft survival was unaffected.

The effect of p22-PHOX (CYBA) polymorphisms on premature coronary artery disease (≤ 40 years of age)

Acute myocardial infarction at a young age is associated with high morbidity and long-term mortality. The NADPH oxidase system as a main source of reactive oxygen species in vascular cells has been implicated in development and progression of coronary artery disease (CAD). In our study, we investigated the effect of polymorphisms in the p22-PHOX (CYBA) gene on CAD in young patients (≤ 40 years). We prospectively recruited 302 subjects into our multi-centre case control study, including 102 young myocardial infarction patients (≤ 40 years) from two high-volume cardiac catheterisation hospitals and frequency-matched them on age, gender, and center to 200 hospital controls in an approximate 2:1 ratio per case patient. The homozygote c.-930A>G promoter polymorphism was significantly more prevalent in the controls than in the infarction patients. In the adjusted logistic regression analysis, we detected a protective effect of the c.-930A>G promoter polymorphism against premature myocardial infarction. Using a log-additive/per-allele model, we detected an unadjusted odds ratio (OR) of 0.63 (95% confidence interval [CI] 0.45-0.9, p-value 0.011). In the adjusted model the association was more pronounced with an OR of 0.5 (95% CI 0.3-0.81, p-value 0.005). The C242T polymorphism and the 640A>G polymorphism did not differ significantly between the study groups. Furthermore we could not detect a significant effect for these polymorphisms in the logistic regression analysis. The present study suggests a protective association between the c.-930A>G promoter polymorphism in the p22-PHOX (CYBA) gene and the development of myocardial infarction in young individuals (≤ 40 years).

Premature myocardial infarction is associated with low serum levels of Wnt-1.

OBJECTIVEnBesides its effects on glucose and lipid metabolism, the Wnt pathway has been increasingly implicated in the regulation of proliferation, migration and survival of vascular cells. In addition, defective Wnt signaling has been identified in a family with autosomal dominant early coronary artery disease. The aim of this study was to investigate whether premature coronary artery disease is associated with features of decreased Wnt signaling.nnnMETHODS AND RESULTSnWe prospectively enrolled 100 consecutive young survivors of myocardial infarction (MI≤40 years of age) from two high-volume cardiac catheterization centers and 100 sex and age matched hospital controls. We determined serum levels of Wnt-1 and its antagonist Dkk-1 by ELISA. MI patients showed significantly lower Wnt-1 levels as compared to controls (151 ng/mL, IQR 38-473 ng/mL vs. 233 ng/mL, IQR 62-1756; p<0.005) whereas Dkk-1 was not different at baseline. Wnt-1 levels remained stable over time, whereas Dkk-1 significantly increased at one-year follow-up from 3557, IQR 2306-5810 pg/mL to 4973, IQR 3293-7093 pg/mL (p<0.001). In the stable phase of the disease, Wnt-1 levels were lower (p<0.005) and Dkk-1 levels were significantly higher (p<0.001) as compared to controls. Wnt-1 at follow-up was associated with glucose, HbA1c, non-HDL-, HDL-cholesterol and triglyceride levels but no other features of the metabolic syndrome.nnnCONCLUSIONnThis study establishes an association between low Wnt-1 and high Dkk-1 serum levels and premature myocardial infarction. Wnt-1 is associated with markers of glucose and lipid metabolism. Further research elucidating the role of Wnt pathways in premature coronary artery disease and metabolic syndrome is warranted.

Markers of bone metabolism in premature myocardial infarction (≤ 40 years of age)

INTRODUCTIONnAcute myocardial infarction (AMI) at young age is a rare disease with a poor prognosis. Bone metabolism parameters such as 1,25 (OH)₂ vitamin D₃, 25 (OH) vitamin D₃ and osteocalcin have been recently implicated in the development of coronary heart disease (CHD). We evaluated the role of these serum markers in a study population of very young AMI survivors (≤ 40 years).nnnMETHODS AND RESULTSnWe prospectively enrolled 302 subjects into our multi-center case control study, including 102 young myocardial infarction patients (≤ 40 years) and 200 control subjects who were frequency-matched on gender and age in an approximate 2:1 ratio per case patient. In the adjusted logistic regression analysis, we used baseline laboratory measurements for the first analysis (acute phase analysis) and measurements from one-year follow-up visits (stable phase analysis). In both, elevated levels of 25 (OH) vitamin D₃ (acute phase: OR per IQR 2.02, 95% CI 1.13-3.58, p = 0.017; stable phase: OR 4.07, 95% CI 1.8-9.21, p = 0.001) and 1,25 (OH)₂ vitamin D₃ (acute phase: OR 2.82, 95% CI 1.7-4.7, p < 0.001; stable phase: OR 4.57, 95% CI 2.31-9.05, p < 0.001) were associated with premature AMI. Conversely, osteocalcin was inversely associated with premature myocardial infarction (acute phase: OR 0.53, 95% CI 0.28-1.03, p = 0.059; stable phase: OR 0.26, 95% CI 0.12-0.6, p < 0.001). The observed associations were independent of the acute phase of myocardial infarction.nnnCONCLUSIONnIn our study, elevated levels of 25 (OH) vitamin D₃ and 1,25 (OH)₂ vitamin D₃, as well as decreased levels of osteocalcin were associated with myocardial infarction in very young patients. The precise mechanism and implications of these findings will have to be elucidated in future studies.

Electrical optimization of cardiac resynchronization in chronic heart failure is associated with improved clinical long-term outcome

Eur J Clin Invest 2010; 40 (8): 678–684