Luit Penninga

Clinical outcomes in randomized trials of off- vs. on-pump coronary artery bypass surgery: systematic review with meta-analyses and trial sequential analyses

AIMS To assess the clinical outcomes of off- vs. on-pump coronary artery bypass surgery in randomized trials. METHODS AND RESULTS We searched electronic databases and bibliographies until June 2007. Trials were assessed for risk of bias. Outcome measures were all-cause mortality, myocardial infarction, stroke, atrial fibrillation, and renewed coronary revascularization at maximum follow-up. We applied trial sequential analysis to estimate the strength of evidence. We found 66 randomized trials. There was no statistically significant differences regarding mortality [relative risk (RR) 0.98; 95% confidence interval (CI) 0.66-1.44], myocardial infarction (RR 0.95; 95% CI 0.65-1.37), or renewed coronary revascularization (RR 1.34; 95% CI 0.83-2.18). We found a significant reduced risk of atrial fibrillation (RR 0.69; 95% CI 0.57-0.83) and stroke (RR 0.53; 95% CI 0.31-0.91) in off-pump patients. However, when continuity correction for zero-event trials was included, the reduction in stroke became insignificant (RR 0.62; 95% CI 0.32-1.19). Trial sequential analysis demonstrated overwhelming evidence supporting that off-pump bypass surgery reduces atrial fibrillation. CONCLUSION Off-pump surgery reduces the risks of postoperative atrial fibrillation compared with on-pump surgery. For death, myocardial infarction, stroke, and renewed coronary revascularization, the evidence is still weak and more low-bias risk trials are needed.

Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-analyses and trial sequential analyses of randomised trials

PurposeWe conducted a systematic review of randomized trials to compare the benefits and harms of tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation.Methods and resultsWe searched electronic databases and bibliographies up to April 2010. Our review followed the Cochrane and PRISMA guidelines. The meta-analysis included 10 randomized trials with 952 patients. Tacrolimus was significantly superior to cyclosporine (both formula-combined) with regard to hypertension (relative risk [RR] 0.8; 95% confidence interval [CI] 0.69–0.93, p = 0.003), hyperlipidaemia (RR 0.57; 95% CI 0.44–0.74, p < 0.0001), hirsutism (RR 0.17 95% CI 0.04–0.62, p = 0.008), and gingival hyperplasia (RR 0.07 95% CI 0.01–0.37, p = 0.002). No significant differences between the two calcineurin inhibitors were found with regard to acute rejections causing haemodynamic instability, diabetes, renal dysfunction, infection, malignancy, or neurotoxicity. Tacrolimus was significantly superior to microemulsion cyclosporine with regard to mortality (RR 0.64; 95% CI 0.42–0.96, p = 0.03), acute severe biopsy-proven rejection (RR 0.71; 95% CI 0.56–0.90, p = 0.004), hyperlipidaemia (RR 0.57; 95% CI 0.41–0.79, p = 0.0009), hirsutism (RR 0.17 95% CI 0.04–0.62, p = 0.008), and gingival hyperplasia (RR 0.07; 95% CI 0.01–0.37, p = 0.002). Tacrolimus was significantly superior to oil-based cyclosporine with regard to hypertension (RR 0.66; 95% CI 0.54–0.80, p < 0.0001), and hyperlipidaemia (RR 0.57; 95% CI 0.38–0.87, p = 0.009).ConclusionTacrolimus seems to be superior to cyclosporine in heart transplant patients with regard to hypertension, hyperlipidaemia, gingival hyperplasia and hirsutism. In addition, tacrolimus seems to be superior to microemulsion cyclosporine in heart transplant patients with regard to a number of outcomes, including death. More trials with a low risk of bias are needed to determine if the results of the present meta-analysis can be confirmed.

Long-term outcome in patients treated with combined heart and liver transplantation for familial amyloidotic cardiomyopathy.

The amyloidogenic transthyretin (ATTR) mutation Leu111Met causes a primarily cardiac amyloidosis: Familial amyloidotic cardiomyopathy (FAC). Combined heart–liver transplantation (CHLTx) is the preferred treatment for patients with heart failure due to familial amyloidosis, but information on outcome of patients with Leu111Met mutation is limited. The aim of this study was to evaluate the long‐term outcome of CHLTx in patients with FAC.

Perforated appendicitis during near‐term pregnancy causing necrotizing fasciitis of the lower extremity: a rare complication of a common disease

A 33‐year‐old woman presented with pain in the right side of the abdomen at 35 weeks of gestation. She was treated for cystitis. A few days later, her abdominal pain had disappeared; however, she had developed pain in the right thigh and fever. She delivered a healthy child, but postpartum her leg symptoms deteriorated. She was found to have a necrotizing fasciitis, which necessitated disarticulation of the hip. The source of the infection was a perforated appendix.

Appendicitis during pregnancy in a Greenlandic Inuit woman; antibiotic treatment as a bridge-to-surgery in a remote area

Appendicitis during pregnancy causes severe diagnostic problems, and is associated with an increase in perforation rate and morbidity compared to that in the normal population. In addition, it may cause preterm birth and fetal loss. In remote areas, appendicitis during pregnancy, besides presenting diagnostic problems, also creates treatment difficulties. In Northern Greenland, geographical distances are vast, and weather conditions can be extreme. We report a case of a Greenlandic Inuit woman who presented with appendicitis during pregnancy. The nearest hospital with surgical and anaesthetic care was located nearly 1200 km away, and, due to extreme weather conditions, she could not be transferred immediately. She was treated with intravenous antibiotic treatment, and after weather conditions had improved, she was transferred by aeroplane and underwent appendicectomy. She recovered without complications. Our case suggests that appendicitis during pregnancy may be treated with antibiotics in remote areas until surgical treatment is available.

Meta-Analysis of Randomised Trials on Laparoscopic Versus Open Surgery for Acute Appendicitis: Has Firm Evidence been Reached?

In their interesting meta-analysis, Ohtani and colleagues have assessed the benefits and harms of laparoscopic surgery versus open surgery for acute appendicitis. One of the most patientcentred outcomes of the meta-analysis is wound infection, and wound infection was also the primary outcome in a Cochrane review comparing laparoscopic versus open appendectomy. Ohtani and colleagues showed that laparoscopic appendectomy reduced the proportion of patients with wound infection with 54 % when compared with open surgery (relative risk (RR), 0.46; 95 % CI, 0.34–0.64; 32 trials; 4,936 patients). However, randomised clinical trials and meta-analyses are at risk of systematic errors due to design problems and risk of bias. To minimise the risk of systematic errors, we assessed the importance of proper randomisation, and a very similar risk reduction in wound infection was found when only the trials with adequate randomisation (both adequate generation of allocation sequence and allocation concealment) were included in the meta-analysis (RR, 0.46; 95% CI, 0.32–0.66; 23 trials; 3,727 patients). In addition to adequate randomisation, other components like adequate blinding, adequate dealing with missing data, and avoidance of selective outcome reporting are important to assess risk of bias in trials. Sufficient blinding in trials comparing laparoscopic appendectomy with open appendectomy is very challenging, if not impossible. When assessing wounds for infection the different types of wounds (number, length and localisation) immediately reveal the type of surgery performed. Only one trial attempted to achieve adequate blinding as at the end of the procedure three wound dressings and an abdominal binder were applied to every patient to blind the patient, the nursing and medical staff and the independent data collector. While this blinding method probably approaches the best we can achieve, and may be sufficient for certain outcomes like for example ‘pain assessment’ or ‘length of hospital stay’, it might still not be adequate to assess ‘wound infection’, and these trials might therefore all be at risk of bias regarding wound infection. In addition to the risk of systematic errors, repetitive meta-analyses are at risk of producing random errors because of sparse data and of multiple looks on the accumulating evidence when new trials emerge. Hence, the question arises, whether we have sufficient evidence for the superiority of laparoscopic surgery for acute appendicitis regarding wound infections from trials with low risk of bias regarding randomisation? Are we convinced and are further trials which compare laparoscopic appendectomy versus open appendectomy superfluous? To minimise random errors, trial sequential analysis is used to calculate the required information size, i.e. the number of participants needed in a meta-analysis to detect or reject a certain intervention effect. The underlying assumption of trial sequential analysis is that significance testing may be performed each time a new trial is added to the metaanalysis. On the basis of the proportion with the outcome in the control group, a chosen risk reduction, the risk for type I errors (5 %) and type II errors (20 %), and the observed L. Penninga : C. Gluud Copenhagen Trial Unit, Centre for Clinical Intervention Research, Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

Non-operative treatment of ruptured ectopic pregnancy

Ruptured ectopic pregnancy often causes abdominal pain, vaginal bleeding and internal haemorrhage; it is a very serious condition and can be life-threatening. Patients with a ruptured ectopic pregnancy are normally treated by surgical intervention. We describe a case of a 20-year-old woman who presented with abdominal pain and vaginal bleeding. Urine human chorionic gonadotropin was positive and on examination she had localised tenderness of the abdomen. Transvaginal ultrasonography revealed a ruptured tubal pregnancy along with blood in the abdomen. The patient was closely monitored and treated conservatively, with a successful outcome. She recovered uneventfully. Our case shows that non-operative treatment of a ruptured ectopic pregnancy may be a possible non-invasive treatment option in highly selected patients.

Haemorrhagic rupture of hepatic simple cysts

Haemorrhagic rupture is a life-threatening complication of a hepatic simple cyst. A 63-year-old man presented with severe acute abdominal pain and a massive haemoperitoneum resulting from haemorrhagic rupture of a large hepatic cyst. The haemorrhagic rupture was aggravated by an overdose of vitamin K-antagonist treatment. CT scans revealed a large hepatic simple cyst. The patient was successfully treated conservatively with resuscitation, transfusion therapy and administration of coagulation agents. To date, there is no clear evidence regarding optimal treatment of haemorrhagic hepatic cyst rupture. The risk of recurrent bleeding from the haemorrhagic hepatic simple cyst, and the need for final treatment to avoid rebleeding either by percutaneous sclerotherapy, endovascular embolisation, surgical cyst resection, or surgical deroofing, is discussed.

Acetazolamide for the prevention of acute mountain sickness: time to move on.

Kayser and colleagues have assessed the benefits and harms of acetazolamide for the prevention of acute mountain sickness in their interesting meta-analysis (Kayser et al., 2012). Compared with placebo, acetazolamide reduced the risk of acute mountain sickness with 49% when all doses were considered, and with 45%, 50%, and 55% when daily doses of 250 mg, 500 mg, and 750 mg acetazolamide were considered (Kayser et al., 2012). However, repetitive metaanalyses are at risk of producing random errors because of sparse data, and due to multiple looks on accumulating evidence when new trials emerge (Wetterslev et al., 2008; Brok et al., 2009). The question arises whether we have sufficient evidence for the efficacy of acetazolamide? Are we convinced and are further trials which compare acetazolamide with placebo superfluous? To minimize random errors, trial sequential analysis can be used to calculate the required information size (i.e., the number of participants needed in a meta-analysis to detect or reject a certain intervention effect, Wetterslev et al., 2008). The underlying assumption of trial sequential analysis is that significance testing may be performed each time a new trial is added to the meta-analysis. On the basis of the risk for type I (5%) and type II (20%) errors, the proportion with the outcome in the control group, the chosen risk reduction of the intervention, and the observed diversity, the diversity-adjusted required information size is calculated and the trial sequential alpha-spending and beta-spending monitoring boundaries are constructed (Wetterslev et al., 2008; Wetterslev et al., 2009; Thorlund et al., 2011). We applied trial sequential analysis on the meta-analysis by Kayser et al., choosing a relative risk reduction (RRR) of 40%. For the comparison of acetazolamide 250 mg versus placebo, we estimated a required information size of 365 patients (currently 603 patients have been studied). For the comparison of acetazolamide 500 mg vs. placebo, we estimated a required information size of 521 patients (currently 995 patients have been studied). For the comparison of acetazolamide 750 mg vs. placebo, we estimated a required information size of 231 patients (currently 272 patients have been studied). For the comparison of all doses of acetazolamide vs. placebo, we estimated a required information size of 347 patients (currently 1870 patients have been studied). Hence, the required information size to accept a 40% RRR was reached for all doses. Even more, the alpha-spending monitoring boundaries were crossed for each individual dose, and for all doses combined before the required information sizes were reached. This means that we may exclude undue risk of random error regarding the evidence for a 40% RRR (being the lower 95% confidence limit of the intervention effect found in the traditional meta-analysis) of acetazolamide for the prevention of acute mountain sickness. Not all of the trials included in the meta-analysis (Kayser et al., 2012) are with low risk of bias (proper randomization, blinding, etc.), so even though random errors can be excluded, the meta-analysis may still be at risk of systematic errors. However, when only including trials with low risk of systematic errors (i.e., trials with low risk of bias according to the Cochrane tool for assessment of risk of bias (Basnyat 2003; Gertsch 2004; Chow 2005; Basnyat 2006; Basnyat 2008; Gertsch 2010; Higgins 2011), acetazolamide was still better than placebo in preventing acute mountain sickness (all doses vs. placebo: RR 0.46; 95% CI 0.37–0.58, and acetazolamide 250 mg (being the dose with the lowest number of adverse effects) vs. placebo: RR 0.54; 95% CI 0.38–0.76). Furthermore, when applying trial sequential analysis on trials with low risk of bias choosing a 40% RRR, the required information size was also reached for all doses (365 patients required, and currently 1165 patients studied) as well as for a daily dose of 250 mg (351 patients required, and currently 428 patients studied). Furthermore, the trial sequential alpha-spending monitoring boundaries for trials with low risk of bias, dose of acetazolamide 250 mg daily, and the anticipation of a 25% RRR (being the lower 95% confidence limit of the intervention effect found in traditional meta-analysis) were crossed. In short, we may exclude both random errors and systematic errors regarding a realistic efficacy of acetazolamide compared with placebo. It is unlikely that new trials will change this evidence. Hence, acetazolamide is useful for the prevention of acute mountain sickness, and it is time to move on beyond doing trials comparing acetazolamide against placebo. Questions that remain to be addressed in future trials include treatment initiation, treatment duration related to mode and speed of ascent, and combinations of acetazolamide with other drugs.

Frostbite—A Case Series From Arctic Greenland

Greenland is not only the largest island in the world, it is also the least densely populated country on the globe. The majority of Greenlands landmass lies within the Arctic Circle. Weather conditions in Arctic areas can be extreme, thus exposing locals and visitors to a high risk of acquiring frostbite injuries. More than two thirds of Greenland is covered by a permanent ice sheet, and temperatures can drop to below -70°C. In addition, frequent storms, occupational exposure, and alcohol all contribute to an increased risk for frostbite injury. Frostbite may cause major morbidity, including tissue loss and limb amputation. Hence, proper diagnosis and treatment of frostbite injuries is of utmost importance. We present 6 cases of frostbite injuries in Greenland, ranging from mild to severe frostbite in both locals and foreign visitors. The cases illustrate some of the known risk factors for frostbite injuries. The etiology, pathophysiology, clinical presentation, and recommended management of frostbite are summarized. Novel treatments for frostbite and frostbite sequelae are discussed in the context of the Greenlandic healthcare system. Furthermore, cultural aspects and reasons for a seemingly low incidence of frostbite injuries in Greenland are explored.