Coronary artery calcium score prediction of all cause mortality and cardiovascular events in people with type 2 diabetes: systematic review and meta-analysis


 

Objective To investigate the association of coronary artery calcium score with all cause mortality and cardiovascular events in people with type 2 diabetes.

Design Systematic review and meta-analysis of observational studies.

Data sources Studies were identified from Embase, PubMed, and abstracts from the 2011 and 2012 annual meetings of the American Diabetes Association, European Association for the Study of Diabetes, American College of Cardiology, and American Heart Association (2011).

Eligibility criteria Prospective studies that evaluated baseline coronary artery calcium score in people with type 2 diabetes and subsequent all cause mortality or cardiovascular events (fatal and non-fatal).

Data extraction Two independent reviewers extracted the data. The predictive value of the coronary artery calcium score was assessed by random effects model.

Results Eight studies were included (n=6521; 802 events; mean follow-up 5.18 years). The relative risk for all cause mortality or cardiovascular events, or both comparing a total coronary artery calcium score of ≥10 with a score of <10 was 5.47 (95% confidence interval 2.59 to 11.53; I2=82.4%, P<0.001). The overall sensitivity of a total coronary artery calcium score of ≥10 for this composite outcome was 94% (95% confidence interval 89% to 96%), with a specificity of 34% (24% to 44%). The positive and negative likelihood ratios were 1.41 (95% confidence interval 1.20 to 1.66) and 0.18 (0.10 to 0.30), respectively. For people with a coronary artery calcium score of <10, the post-test probability of the composite outcome was about 1.8%, representing a 6.8-fold reduction from the pretest probability. Four studies evaluated cardiovascular events as the outcome (n=1805; 351 events). The relative risk for cardiovascular events comparing a total coronary artery calcium score of ≥10 with a score of <10 was 9.22 (2.73 to 31.07; I2=76.7%, P=0.005). The positive and negative likelihood ratios were 1.67 (1.30 to 2.17) and 0.11 (0.04 to 0.29), respectively.

Conclusion In people with type 2 diabetes, a coronary artery calcium score of ≥10 predicts all cause mortality or cardiovascular events, or both, and cardiovascular events alone, with high sensitivity but low specificity. Clinically, the finding of a coronary artery calcium score of <10 may facilitate risk stratification by enabling the identification of people at low risk within this high risk population.

Discussion

In people with type 2 diabetes, the presence of a coronary artery calcium score of ≥10 predicts both all cause mortality and cardiovascular events as well as cardiovascular events alone, with high sensitivity but low specificity. The negative likelihood ratio of the coronary artery calcium score for these outcomes was strikingly low (0.18 for all cause mortality and cardiovascular events, and 0.11 for cardiovascular events). Indeed, our evaluation of risk estimates through the Bayes normogram suggests that the coronary artery calcium score may be especially helpful in clinical practice when it is below 10.

Our meta-analyses showed that the coronary artery calcium score might have a role in predicting events in people with type 2 diabetes. The findings of an increased relative risk for all cause mortality and cardiovascular events and cardiovascular events alone were consistent. The exploratory analysis of heterogeneity identified the variables associated with higher variance between studies, especially for cardiovascular events alone (where the sensitivity analysis eliminated the heterogeneity). We used the likelihood ratio as an alternative statistic because of its clinical applicability. Interestingly, we found a low negative likelihood ratio, in the range (that is, 0.1) that Deeks and Altman have previously suggested as providing strong evidence for ruling out the occurrence of an outcome in most circumstances.37

When evaluating a predictor of adverse outcomes, it is recognised that a useful predictor should have a favourable risk-benefit ratio, reasonable cost, acceptability, and convenience. In addition, to make screening worthwhile an effective treatment should be available, and this treatment should not be equally effective in everyone.38 In this context, screening using the coronary artery calcium score is a convenient and non-invasive test, although it involves exposure to ionising radiation of about 1 millisieverts (which is comparable to screening mammography).39 No formal cost effectiveness analyses have been done on the coronary artery calcium score in people with type 2 diabetes integrating risk, benefits, and cost; however, the current findings raise the possibility that screening using the coronary artery calcium score may be cost effective in some subgroups of people with diabetes. Moreover, a previous report showed that patient awareness of an abnormal score was associated with increased adherence to aspirin use and lifestyle changes,40 suggesting that, besides risk stratification, the coronary artery calcium score might help to support behavioural modification.

The American Heart Association has supported the use of the coronary artery calcium score quantification in people at intermediate risk to improve risk assessment (class IIb recommendation).41 Conversely, the American Diabetes Association does not recommend its routine use in people with type 2 diabetes because the overall balance of risk, benefits, and cost of such an approach in people without symptoms remains controversial.1 In light of the lack of previous evidence to support the routine use of the coronary artery calcium score as a screening test in people with type 2 diabetes, we feel that the current meta-analysis is much needed and holds implications for the design of future studies. In particular, the finding of such a low likelihood ratio suggests that a coronary artery calcium score of <10 might help with risk stratification of people with type 2 diabetes and potentially would change prevention strategies in those people. In fact, it has been suggested that the coronary artery calcium score may help to identify people with diabetes who may benefit from aspirin therapy among those without a clear indication based on current guidelines.13 Most importantly, if we consider that the prevalence of a coronary artery calcium score of <10 was 28.5% in our study population, the current findings might have an important impact on clinical care. Indeed, considering the worldwide prevalence of 346 million cases of type 2 diabetes,42 these data suggest that about 86.5 million people with type 2 diabetes would have a coronary artery calcium score of <10 and hence a low risk of cardiovascular events. In addition, a score of <10 has been observed in a significant proportion of people with diabetes at intermediate risk on pretest assessment, a subgroup of people who would most benefit from the coronary artery calcium score test.13 33 In this way, screening using the coronary artery calcium score may facilitate clinical risk stratification by identifying a sizeable subgroup of people at low risk within the high risk population of people with diabetes.

The concept of a low risk subgroup within the population of people with diabetes has been demonstrated in a previous report that showed a similar risk of all cause mortality between people with and without diabetes who had no coronary artery calcium score at baseline (survival 98.8% v 99.4% over five years, P=0.49).30 These data reinforce the results of our meta-analysis, in which a coronary artery calcium score of <10 was indicative of low risk for future events in people with diabetes. In addition, in the same way that the coronary artery calcium score adds to current predictive scores in the general population,6 these data raise the possibility that incorporation of coronary artery calcium score into existing risk scores for people with diabetes might improve risk prediction and hence warrants further investigation.

Limitations of this review

A limitation of our meta-analysis is that an analysis of additional risk stratification beyond current available risk scores for people with type 2 diabetes could not be performed owing to the absence of such studies. Secondly, most studies did not take into consideration the use of drugs (that is, aspirin and lipid lowering drugs) that could interfere with the estimates of event rate prediction based on the coronary artery calcium score. Nevertheless, as all studies were performed after 2004, we believe that the people were possibly treated similarly based on current clinical practice recommendations. Thirdly, only three studies reported baseline glycated haemoglobin A1c and duration of diabetes. However, although these covariates could not be included in metaregression analyses, our models were able to identify the studies that better explained the variance between studies. Of note, although most studies measured the coronary artery calcium score using the same technique, differences in the protocol for obtaining the scores could also have contributed to the variance between studies. Finally, we recognise that publication bias and the quality limitations of individual studies may still be relevant despite our best efforts to conduct a comprehensive search and the lack of statistical evidence of bias. The subjective nature of the Newcastle-Ottawa scale by which the quality of studies was assessed should also be noted.

Our meta-analysis strongly suggests that the coronary artery calcium score warrants further investigation as a prediction tool in people with type 2 diabetes. In particular, randomised controlled trials evaluating the impact of screening using the coronary artery calcium score on mortality are needed. Another point to consider in future studies is that atherosclerosis is a dynamic process, as shown by studies documenting both progression and regression of plaque.43 44 45 Glucose levels are an independent risk factor for progression of coronary artery calcium score,46 and people with type 2 diabetes have been shown to have a higher rate of progression than those without diabetes.47 Thus, the optimal frequency of screening using the coronary artery calcium score also needs to be established.

Conclusion

The coronary artery calcium score predicts all cause mortality and cardiovascular events and cardiovascular events alone in people with type 2 diabetes. People with a coronary artery calcium score of <10 were 6.8 times less likely to have cardiovascular event. Taken together, our meta-analysis strongly suggests the need for further investigation of the utility of using the coronary artery calcium score, particularly because of the implications that a negative screening test may hold for clinical risk stratification and preventive management in this population.

What is already known on this topic

  • The coronary artery calcium (CAC) score has been shown to predict the risk for cardiovascular events and facilitate reclassification of people from intermediate to low or high risk in large prospective studies of the general population
  • However, most of these studies excluded people with diabetes
  • The role of the CAC score in people with type 2 diabetes is unclear and given the broad range of cardiovascular risk observed in people with diabetes, this population warrants focused investigation on the predictive capacity of the CAC score
  • A CAC score of ≥10 predicted all cause mortality or cardiovascular events, or both compared with a score of <10, with high sensitivity but low specificity
  • For people with a CAC score of <10, the post-test probability of all cause mortality or cardiovascular events was reduced by 6.8-fold from their pretest probability
  • In people with diabetes, the finding of a CAC score of <10 may facilitate risk stratification by enabling the identification of low risk people within this otherwise high risk population

What this study adds

Source: BMJ

 

 

Breast cancer detection and survival among women with cosmetic breast implants: systematic review and meta-analysis of observational studies.


Abstract

Objectives To evaluate whether the stage distribution among women diagnosed as having breast cancer differs between those who have received breast implants for cosmetic purposes and those with no implants and to evaluate whether cosmetic breast augmentation before the detection of breast cancer is a predictor of post-diagnosis survival.

Design Systematic review of observational studies with two meta-analyses.

Data sources Systematic search of the literature published before September 2012 conducted in Medline, Embase, Global health, CINAHL, IPAB, and PsycINFO.

Study selection Eligible publications were those that included women diagnosed as having breast cancer and who had had augmentation mammaplasty for cosmetic purposes.

Results The overall odds ratio of the first meta-analysis based on 12 studies was 1.26 (95% confidence interval 0.99 to 1.60; P=0.058; I2=35.6%) for a non-localized stage of breast cancer at diagnosis comparing women with implants who had breast cancer and women without implants who had breast cancer. The second meta-analysis, based on five studies, evaluated the relation between cosmetic breast implantation and survival. This meta-analysis showed reduced survival after breast cancer among women who had implants compared with those who did not (overall hazard ratio for breast cancer specific mortality 1.38, 95% confidence interval 1.08 to 1.75).

Conclusions The research published to date suggests that cosmetic breast augmentation adversely affects the survival of women who are subsequently diagnosed as having breast cancer. These findings should be interpreted with caution, as some studies included in the meta-analysis on survival did not adjust for potential confounders. Further investigations are warranted regarding diagnosis and prognosis of breast cancer among women with breast implants.

Discussion

This systematic review suggests that women with cosmetic breast implants have later stage tumors at diagnosis of breast cancer. In our second meta-analysis, the results show a higher risk of breast cancer specific mortality among women with breast cancer who have implants compared with women with breast cancer without implants. Nevertheless, the overall estimate should still be interpreted with caution because this meta-analysis included a relatively small number of studies. Of concern, three of five studies had unadjusted hazard ratios (not adjusted for age at diagnosis, or period of diagnosis) and all five studies were unadjusted for other potential confounding factors such as body mass index, which could translate into a biased estimate of the summary hazard ratio. A lack of adjustment for body mass index has previously been shown to lead to underestimation of the association between cosmetic breast implants and breast cancer mortality.18 Moreover, one study included in this meta-analysis assessed overall mortality rather than breast cancer specific mortality,39 which could have biased our summary estimate towards the null. The small number of studies and insufficient amount of follow-up time in these studies are suspected to limit statistical power to clearly evaluate survival rate patterns among augmented women. Given the limited evidence, no conclusion regarding breast cancer specific survival can be drawn and continued follow-up to further evaluate this question is particularly relevant.

Source: BMJ

Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study.


Abstract

Objectives To quantify the diagnostic accuracy of selected inflammatory markers in addition to symptoms and signs for predicting pneumonia and to derive a diagnostic tool.

Design Diagnostic study performed between 2007 and 2010. Participants had their history taken, underwent physical examination and measurement of C reactive protein (CRP) and procalcitonin in venous blood on the day they first consulted, and underwent chest radiography within seven days.

Setting Primary care centres in 12 European countries.

Participants Adults presenting with acute cough.

Main outcome measures Pneumonia as determined by radiologists, who were blind to all other information when they judged chest radiographs.

Results Of 3106 eligible patients, 286 were excluded because of missing or inadequate chest radiographs, leaving 2820 patients (mean age 50, 40% men) of whom 140 (5%) had pneumonia. Re-assessment of a subset of 1675 chest radiographs showed agreement in 94% (κ 0.45, 95% confidence interval 0.36 to 0.54). Six published “symptoms and signs models” varied in their discrimination (area under receiver operating characteristics curve (ROC) ranged from 0.55 (95% confidence interval 0.50 to 0.61) to 0.71 (0.66 to 0.76)). The optimal combination of clinical prediction items derived from our patients included absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever, with an ROC area of 0.70 (0.65 to 0.75). Addition of CRP at the optimal cut off of >30 mg/L increased the ROC area to 0.77 (0.73 to 0.81) and improved the diagnostic classification (net reclassification improvement 28%). In the 1556 patients classified according to symptoms, signs, and CRP >30 mg/L as “low risk” (<2.5%) for pneumonia, the prevalence of pneumonia was 2%. In the 132 patients classified as “high risk” (>20%), the prevalence of pneumonia was 31%. The positive likelihood ratio of low, intermediate, and high risk for pneumonia was 0.4, 1.2, and 8.6 respectively. Measurement of procalcitonin added no relevant additional diagnostic information. A simplified diagnostic score based on symptoms, signs, and CRP >30 mg/L resulted in proportions of pneumonia of 0.7%, 3.8%, and 18.2% in the low, intermediate, and high risk group respectively.

Conclusions A clinical rule based on symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough performed best in patients with mild or severe clinical presentation. Addition of CRP concentration at the optimal cut off of >30 mg/L improved diagnostic information, but measurement of procalcitonin concentration did not add clinically relevant information in this group.

Discussion

Main findings

Pneumonia was diagnosed by chest x radiography in 140 (5%) of the 2820 patients presenting to primary care with acute cough. The optimal combination of symptoms and signs for predicting pneumonia was absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever. Signs and symptoms were useful in correctly identifying patients with a “low” (<2.5%) or “high” (>20%) diagnostic risk in 26% of patients. In the 74% of patients in whom diagnostic doubt remained (estimated risk 2.5%-20%), measurement of C reactive protein (CRP) concentration helped to correctly exclude pneumonia. A simplified diagnostic score based on symptoms, signs, and CRP concentration resulted in proportions of pneumonia of 0.7%, 4%, and 18% in the low, intermediate, and high risk group, respectively. Measurement of procalcitonin concentration had no clinically relevant added value in this setting.

Strengths and limitations

This is the first study to quantify the independent diagnostic value of symptoms, signs, and additional diagnostic value of inflammatory markers for pneumonia in patients presenting with acute cough in primary care that included an adequate number of cases of pneumonia. All blood samples were analysed in the same laboratory with standardised procedures. Serum CRP and procalcitonin concentrations were measured by conventional venous blood tests in a diagnostic laboratory and not with a point of care test. The added value of CRP might be different and could be lower when measured with a point of care test in general practice. Nonetheless, agreement between point of care test results and a conventional reference test has been shown to be good.44

Given how common lower respiratory tract infections are, many more eligible patients presented during the recruitment period than were approached about participation in this study, and therefore we probably did not achieve the goals of recruiting all consecutive, eligible patients. Nevertheless, we do not believe that there was important clinical selection bias because feedback from recruiting clinicians during and after the study was that the time required to recruit and assess each patient made sequential recruitment of every eligible patient impossible.

Chest radiographs were examined by local radiologists. We attempted to increase uniformity in assessment by implementing a protocol for reporting. While there was some variability between observers, the moderate unweighted κ of 0.45 was similar to that reported in other studies.18 20

We did not attempt to distinguish between bacterial and viral pneumonia as this is not feasible in routine primary care.14 45 All available relevant guidelines advocate identification of patients with pneumonia and treatment with antibiotics without further aetiological testing.14

Comparison with other studies

Absence of a runny nose and presence of dry cough, breathlessness, chest pain, diarrhoea, fever, and crackles have previously been found to have diagnostic value for pneumonia in primary care populations.7 9 “Tachycardia” and “diminished vesicular breathing” have diagnostic value in secondary care populations.3 6 8 11 We were able to confirm the predictive value of most of these items, apart from chest pain and diarrhoea. Differences between our findings and those from previous studies could relate to the difference in prevalence of pneumonia, inclusion criteria, and outcome definition.

Our finding that CRP concentration can be low in people with pneumonia is not new. Flanders and colleagues reported on a small subgroup of patients with pneumonia who had a CRP of less than 11 mg/L.3 In the 54 patients with pneumonia with low CRP in our study, the estimated diagnostic risk of pneumonia was high (n=3) or intermediate (n=51) based on history and physical examination results as defined in our model. These findings emphasise that CRP test results should be interpreted together with clinical findings.

Of the factors known to lower CRP—such as steroid use46 and duration of disease47—only steroid use (including both oral and inhaled steroids) was significantly more prevalent in the group of patients with pneumonia with low CRP concentration. Exclusion of all steroid users from our analyses resulted in a similar association between CRP concentration and pneumonia.

Procalcitonin concentrations in our study were higher in patients with pneumonia and comparable with previous findings in patients with lower respiratory tract infection in primary care.17 48 They did not, however, add meaningful diagnostic information. Holm and colleagues showed a clear association between procalcitonin concentration and radiographic pneumonia as well as bacterial infection,17 but the positive predictive value was too low to be useful in clinical practice. Our findings support this conclusion. Moreover, Holm and colleagues studied a population with a higher prevalence of pneumonia (13%) and did not combine history and physical examination with procalcitonin test results.17

Implications for practice and conclusions

Although the diagnostic “symptoms and signs” model presented in this study assigned an intermediate diagnostic risk of pneumonia to most patients, history taking and physical examination alone enabled general practitioners to correctly identify a small group of patients at high risk. Chest radiography and/or (empirical) antibiotic treatment should therefore be considered in these patients. In these more severely ill patients, point of care tests, including CRP, do not seem to be useful. In patients with a low risk of pneumonia based on symptoms and signs, it seems justified to withhold further diagnostic investigation and not to treat with antibiotics.

CRP has additional diagnostic value in patients with an intermediate diagnostic risk of pneumonia as determined by symptoms and signs alone, especially in appropriately excluding pneumonia. Procalcitonin has no additional diagnostic value in primary care.

The simplified score derived from the regression models is more suitable for uptake in daily care than the regression models. The downside of the simplified score is that it is less precise and contains less diagnostic information. To determine whether our diagnostic model improves clinical outcomes in everyday practice would require an implementation study in which general practitioners use point of care CRP testing with outcomes such as patient recovery and the unnecessary prescription of antibiotics. Further research should also determine the performance of CRP in other settings where pneumonia is more prevalent or where patients are more severely ill.

What is already known on this topic

  • Studies have evaluated the diagnostic accuracy of signs and symptoms for pneumonia, but there is limited evidence applicable to primary care
  • The added diagnostic value of C reactive protein (CRP) and procalcitonin concentrations to clinical signs and symptoms is unknown
  • Symptoms and signs (absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever) have moderate diagnostic accuracy for pneumonia in patients who present in primary care with acute cough
  • CRP concentration at the optimal threshold of >30 mg/L adds some diagnostic information by increasing diagnostic certainty in the patients when doubt remains after history and physical examination
  • Procalcitonin concentration adds no clinically relevant information in primary care

What this study adds

Source: BMj

 

 

Breast cancer detection and survival among women with cosmetic breast implants: systematic review and meta-analysis of observational studies


 

Objectives To evaluate whether the stage distribution among women diagnosed as having breast cancer differs between those who have received breast implants for cosmetic purposes and those with no implants and to evaluate whether cosmetic breast augmentation before the detection of breast cancer is a predictor of post-diagnosis survival.

Design Systematic review of observational studies with two meta-analyses.

Data sources Systematic search of the literature published before September 2012 conducted in Medline, Embase, Global health, CINAHL, IPAB, and PsycINFO.

Study selection Eligible publications were those that included women diagnosed as having breast cancer and who had had augmentation mammaplasty for cosmetic purposes.

Results The overall odds ratio of the first meta-analysis based on 12 studies was 1.26 (95% confidence interval 0.99 to 1.60; P=0.058; I2=35.6%) for a non-localized stage of breast cancer at diagnosis comparing women with implants who had breast cancer and women without implants who had breast cancer. The second meta-analysis, based on five studies, evaluated the relation between cosmetic breast implantation and survival. This meta-analysis showed reduced survival after breast cancer among women who had implants compared with those who did not (overall hazard ratio for breast cancer specific mortality 1.38, 95% confidence interval 1.08 to 1.75).

Conclusions The research published to date suggests that cosmetic breast augmentation adversely affects the survival of women who are subsequently diagnosed as having breast cancer. These findings should be interpreted with caution, as some studies included in the meta-analysis on survival did not adjust for potential confounders. Further investigations are warranted regarding diagnosis and prognosis of breast cancer among women with breast implants.

Discussion

This systematic review suggests that women with cosmetic breast implants have later stage tumors at diagnosis of breast cancer. In our second meta-analysis, the results show a higher risk of breast cancer specific mortality among women with breast cancer who have implants compared with women with breast cancer without implants. Nevertheless, the overall estimate should still be interpreted with caution because this meta-analysis included a relatively small number of studies. Of concern, three of five studies had unadjusted hazard ratios (not adjusted for age at diagnosis, or period of diagnosis) and all five studies were unadjusted for other potential confounding factors such as body mass index, which could translate into a biased estimate of the summary hazard ratio. A lack of adjustment for body mass index has previously been shown to lead to underestimation of the association between cosmetic breast implants and breast cancer mortality.18 Moreover, one study included in this meta-analysis assessed overall mortality rather than breast cancer specific mortality,39 which could have biased our summary estimate towards the null. The small number of studies and insufficient amount of follow-up time in these studies are suspected to limit statistical power to clearly evaluate survival rate patterns among augmented women. Given the limited evidence, no conclusion regarding breast cancer specific survival can be drawn and continued follow-up to further evaluate this question is particularly relevant.

Source: BMJ

Hepatocellular Carcinoma after the Fontan Procedure.


Long-term hepatic dysfunction is an increasingly recognized complication of corrective surgery for complex cyanotic congenital heart disease.1 We report four cases of hepatocellular carcinoma in patients with congenital heart disease with univentricular physiology that was palliated by means of the Fontan procedure (

Patient 1, a 32-year-old woman with a cirrhotic liver, was shown to have a 4-cm hepatocellular carcinoma on biopsy. She underwent transarterial chemoembolization and was put on the waiting list for combined heart and liver transplantation.

Patient 2, a 24-year-old man with portal-vein thrombosis, ascites, and innumerable bilobar hepatic nodules, was shown to have neither cirrhosis nor hepatocellular carcinoma on targeted biopsies. A third biopsy revealed well-differentiated hepatocellular carcinoma. He died from metastatic hepatocellular carcinoma.

Patient 3, a 33-year-old man with a dominant liver nodule, had findings on imaging that were characteristic of hepatocellular carcinoma. He was put on the waiting list for combined heart and liver transplantation and underwent radioembolization at another institution. He had massive gastrointestinal bleeding from a hepatic-artery pseudoaneurysm and subsequently died.

Patient 4, a 42-year-old woman with hepatitis C virus infection, advanced liver fibrosis, and two lesions characteristic of hepatocellular carcinoma, underwent successful chemoembolization after being put on the waiting list for combined heart and liver transplantation.

Patients with congenital heart disease who undergo the Fontan procedure may represent a novel group for screening for liver disease. Surveillance for hepatocellular carcinoma may be needed in such patients, especially if the alpha-fetoprotein level is elevated.2 Cirrhosis may develop in persons under the age of 25 years approximately 11 to 15 years after a Fontan procedure; an incidence of cancer of 1.5 to 5.0% per year is estimated on the basis of previous studies. Cirrhosis, a potential prerequisite for hepatocellular carcinoma, may develop because of repetitive mechanical stretch and compression (passive congestion) and tissue hypoxia (low cardiac output) related either to the circulation created by the Fontan procedure or to chronically elevated right atrial pressure.3 The interval for screening for liver disease is unknown.2

Diagnosing hepatocellular carcinoma in patients with congenital heart disease is difficult because hyperenhancing nodules are often present in such patients.4 In patients with cardiac failure and intrahepatic vascular shunts, the typical arterial enhancing pattern of hepatocellular carcinoma may not be obvious. Surgical resection of the carcinoma may be limited by portal hypertension. Local–regional therapy may be limited by the presence of cardiac pacemakers (radiofrequency ablation), extrahepatic shunts (radioembolization), and abnormal vasculature (chemoembolization). Liver transplantation is limited by cardiac function (hypoxemia, pulmonary hypertension, and elevated right atrial pressure). Combined heart and liver transplantation may be feasible, but experience in such cases is limited.5Since corrective surgery for patients with univentricular physiology has substantially reduced childhood mortality associated with complex cyanotic congenital heart disease, urgent attention and vigilance are needed to avoid a similar premature fate in early adulthood.

Source: NEJM

 

 

 

Surgery versus Physical Therapy for a Meniscal Tear and Osteoarthritis


 

Whether arthroscopic partial meniscectomy for symptomatic patients with a meniscal tear and knee osteoarthritis results in better functional outcomes than nonoperative therapy is uncertain.

METHODS

We conducted a multicenter, randomized, controlled trial involving symptomatic patients 45 years of age or older with a meniscal tear and evidence of mild-to-moderate osteoarthritis on imaging. We randomly assigned 351 patients to surgery and postoperative physical therapy or to a standardized physical-therapy regimen (with the option to cross over to surgery at the discretion of the patient and surgeon). The patients were evaluated at 6 and 12 months. The primary outcome was the difference between the groups with respect to the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical-function score (ranging from 0 to 100, with higher scores indicating more severe symptoms) 6 months after randomization.

RESULTS

In the intention-to-treat analysis, the mean improvement in the WOMAC score after 6 months was 20.9 points (95% confidence interval [CI], 17.9 to 23.9) in the surgical group and 18.5 (95% CI, 15.6 to 21.5) in the physical-therapy group (mean difference, 2.4 points; 95% CI, −1.8 to 6.5). At 6 months, 51 active participants in the study who were assigned to physical therapy alone (30%) had undergone surgery, and 9 patients assigned to surgery (6%) had not undergone surgery. The results at 12 months were similar to those at 6 months. The frequency of adverse events did not differ significantly between the groups.

CONCLUSIONS

In the intention-to-treat analysis, we did not find significant differences between the study groups in functional improvement 6 months after randomization; however, 30% of the patients who were assigned to physical therapy alone underwent surgery within 6 months.

Source: NEJM

 

Penicillin to Prevent Recurrent Leg Cellulitis

BACKGROUND

Cellulitis of the leg is a common bacterial infection of the skin and underlying tissue. We compared prophylactic low-dose penicillin with placebo for the prevention of recurrent cellulitis.

METHODS

We conducted a double-blind, randomized, controlled trial involving patients with two or more episodes of cellulitis of the leg who were recruited in 28 hospitals in the United Kingdom and Ireland. Randomization was performed according to a computer-generated code, and study medications (penicillin [250 mg twice a day] or placebo for 12 months) were dispensed by a central pharmacy. The primary outcome was the time to a first recurrence. Participants were followed for up to 3 years. Because the risk of recurrence was not constant over the 3-year period, the primary hypothesis was tested during prophylaxis only.

RESULTS

A total of 274 patients were recruited. Baseline characteristics were similar in the two groups. The median time to a first recurrence of cellulitis was 626 days in the penicillin group and 532 days in the placebo group. During the prophylaxis phase, 30 of 136 participants in the penicillin group (22%) had a recurrence, as compared with 51 of 138 participants in the placebo group (37%) (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P=0.01), yielding a number needed to treat to prevent one recurrent cellulitis episode of 5 (95% CI, 4 to 9). During the no-intervention follow-up period, there was no difference between groups in the rate of a first recurrence (27% in both groups). Overall, participants in the penicillin group had fewer repeat episodes than those in the placebo group (119 vs. 164, P=0.02 for trend). There was no significant between-group difference in the number of participants with adverse events (37 in the penicillin group and 48 in the placebo group, P=0.50).

CONCLUSIONS

In patients with recurrent cellulitis of the leg, penicillin was effective in preventing subsequent attacks during prophylaxis, but the protective effect diminished progressively once drug therapy was stopped.

Source: NEJM

 

Cardiovascular Risks with Azithromycin and Other Antibacterial Drugs.


In 2011, approximately 40.3 million people in the United States (roughly one eighth of the population) received an outpatient prescription for the macrolide azithromycin, according to IMS Health. During that year, we at the Food and Drug Administration (FDA) reviewed the labels of azithromycin and other approved macrolide antibacterials in view of cardiovascular risks that had become evident from published studies and reports emerging through postmarketing surveillance. On the basis of its review, the FDA approved revisions to azithromycin product labels regarding risks of QT-interval prolongation and the associated ventricular arrhythmia torsades de pointes. The revised labels advise against using azithromycin in patients with known risk factors such as QT-interval prolongation, hypokalemia, hypomagnesemia, bradycardia, or use of certain antiarrhythmic agents, including class IA (e.g., quinidine and procainamide) and class III (e.g., dofetilide, amiodarone, and sotalol) — drugs that can prolong the QT interval. In March 2013, the FDA announced that azithromycin labels had been further revised to reflect the results of a clinical study showing that azithromycin can prolong the corrected QT interval.

In a 2012 observational study involving Tennessee Medicaid patients, Ray et al.1 quantified the risk of death from cardiovascular causes associated with azithromycin as compared with other antibacterial drugs or nonuse. The study showed that the risks of death, both from any cause and from cardiovascular causes, associated with azithromycin were greater than those associated with amoxicillin. For every 21,000 outpatient prescriptions written for azithromycin, one cardiovascular death occurred in excess of those observed with the same number of amoxicillin prescriptions. The excess risk over amoxicillin varied considerably according to cardiovascular risk factors; the researchers estimated that there was one excess cardiovascular death per 4100 prescriptions among patients at high cardiovascular risk but less than one per 100,000 among patients with lower cardiovascular risk.

The study by Ray et al. has limitations that are intrinsic to observational, nonrandomized clinical studies. In particular, nonrandomized studies cannot exclude the possibility that patients receiving a drug under evaluation differ from control patients in some important but undetected way, causing bias in the results. Such confounding may bias comparisons not only between patients receiving antibacterial drugs and those receiving no antibacterials but also between patients receiving different antibacterials. Although Ray et al. used appropriate analytic methods to address potential confounding, we cannot know for certain whether these methods were fully successful. Replication of the authors’ results, through analysis of a distinct data set, would provide more confidence in the finding of increased cardiovascular mortality among patients receiving azithromycin.

Despite such caveats, the results presented by Ray et al. warrant serious attention. A chief strength of the results is the time-limited pattern of the risk: the azithromycin-associated increase in the rates of death from any cause and from cardiovascular causes spanned days 1 through 5, reflecting the typical 5-day duration of azithromycin administration (e.g., Zithromax Z-Pak). On days 6 through 10, an elevated risk of death from cardiovascular causes was no longer detected. This pattern is consistent with the timing of peak plasma azithromycin concentrations and the concomitant risk of QT-interval prolongation. The elevated risk was statistically significant, regardless of whether azithromycin treatment was compared with amoxicillin or with nonuse of an antibacterial drug. Furthermore, the observed excess mortality was attributable solely to cardiovascular deaths and, in particular, to sudden cardiac death; although sudden cardiac death can result from causes other than arrhythmias, an increase in deaths in this category would be the pattern expected from an arrhythmogenic, QT-interval–prolonging drug. Also, the azithromycin-associated risk was higher among patients with cardiovascular disorders, which is consistent with a drug-related arrhythmia.

A new study by Svanström and colleagues (pages 1704–1712), using Danish national health care data, found no difference between azithromycin and penicillin V in the 5-day risk of cardiovascular death (relative risk, 0.93; 95% confidence interval [CI], 0.56 to 1.55). However, the upper bound of the 95% confidence interval does not exclude an increased risk of as much as 55%. As Svanström et al. point out, the population they studied differed from that studied by Ray et al. with respect to the baseline risk of death and cardiovascular risk factors. Overall, the Danish patients had better cardiovascular health than the Tennessee Medicaid patients. In a subgroup analysis of patients with a history of cardiovascular disease, the risk ratio for azithromycin versus penicillin V was greater than 1, though the difference was not statistically significant (relative risk, 1.35; 95% CI, 0.69 to 2.64). Svanström et al. conclude that their results do not conflict with those of Ray et al. Rather, the effect on cardiovascular mortality may be limited to patients with cardiovascular disease.

One must, of course, weigh any observed drug-associated risk against clinical benefits, so it’s appropriate to consider the possibility that certain offsetting benefits of azithromycin may not have been reflected in the risk data analyzed by Ray et al. For example, other studies have suggested that macrolides have an advantage over other antibacterial agents in terms of overall survival from community-acquired pneumonia. In a recent Canadian observational study, researchers followed 2973 outpatients with community-acquired pneumonia and found significantly lower 30-day mortality among patients receiving macrolides than among those receiving fluoroquinolones (adjusted odds ratio, 0.28; 95% CI, 0.09 to 0.86).2 A recent meta-analysis of observational studies showed a statistically significant 25% difference in mortality among hospitalized patients with community-acquired pneumonia favoring macrolides over nonmacrolide antibacterials.3 Such findings, which must be considered with due regard for the limits of observational studies, do not necessarily contradict the results of Ray et al. Past the 5-day period of risk of azithromycin-associated cardiovascular death, the drug might reduce the longer-term (e.g., more-than-30-day) rate of death due to pneumonia. Pneumonia was an uncommon indication among the Tennessee Medicaid patients treated with azithromycin.

Clinicians must consider the arrhythmogenic potential not only of azithromycin but also of potential alternative antibacterial drugs. An earlier study showed an association between the use of erythromycin and sudden cardiac death, augmented by concomitant use of inhibitors of the cytochrome P-450 3A isozymes that metabolize erythromycin.4 Labels for erythromycin and clarithromycin include warnings regarding QT-interval prolongation and arrhythmias. All labels for fluoroquinolone products similarly have warnings regarding QT-interval prolongation, and grepafloxacin was withdrawn from the market because of that risk. A recent observational study of elderly residents of Quebec, Canada, showed an association between outpatient fluoroquinolone use and serious arrhythmias (as defined by hospital discharge diagnoses of ventricular arrhythmia or sudden or unattended death).5 And although Ray et al. found the risk of cardiovascular death to be greater with azithromycin than with ciprofloxacin, they found the risk with levofloxacin similar to that with azithromycin. The authors interpreted this similarity as evidence that levofloxacin may be proarrhythmic; however, levofloxacin was not implicated as proarrhythmic in the Canadian study.

We investigated the most common ambulatory indications for azithromycin by analyzing data from a survey conducted by Encuity Research of approximately 3200 office-based physicians for the decade from 2002 through 2011. Across all age groups of patients, the two most common indications for azithromycin were chronic sinusitis and bronchitis.

Azithromycin was the leading antibacterial drug for outpatient treatment of bronchitis during this period (even if amoxicillin is combined with amoxicillin–clavulanate). For chronic sinusitis, azithromycin ranked second after amoxicillin. Because the indications are reported by the prescribing physicians, these data don’t allow us to assess the diagnostic certainty regarding the infections being treated.

The risks and benefits of antibacterial therapy should be considered in prescribing decisions. Pharmacologic and epidemiologic data point to lethal arrhythmias as a potential consequence of QT-interval prolongation with use of azithromycin, other macrolides, and fluoroquinolones. This possibility should give clinicians pause when they’re considering prescribing antibacterial drugs, especially for patients with preexisting cardiovascular risk factors or clinical conditions in which antibacterial drug therapy has limited benefits.

Source: NEJM

 

Cardiovascular Risks with Azithromycin and Other Antibacterial Drugs.


In 2011, approximately 40.3 million people in the United States (roughly one eighth of the population) received an outpatient prescription for the macrolide azithromycin, according to IMS Health. During that year, we at the Food and Drug Administration (FDA) reviewed the labels of azithromycin and other approved macrolide antibacterials in view of cardiovascular risks that had become evident from published studies and reports emerging through postmarketing surveillance. On the basis of its review, the FDA approved revisions to azithromycin product labels regarding risks of QT-interval prolongation and the associated ventricular arrhythmia torsades de pointes. The revised labels advise against using azithromycin in patients with known risk factors such as QT-interval prolongation, hypokalemia, hypomagnesemia, bradycardia, or use of certain antiarrhythmic agents, including class IA (e.g., quinidine and procainamide) and class III (e.g., dofetilide, amiodarone, and sotalol) — drugs that can prolong the QT interval. In March 2013, the FDA announced that azithromycin labels had been further revised to reflect the results of a clinical study showing that azithromycin can prolong the corrected QT interval.

In a 2012 observational study involving Tennessee Medicaid patients, Ray et al.1 quantified the risk of death from cardiovascular causes associated with azithromycin as compared with other antibacterial drugs or nonuse. The study showed that the risks of death, both from any cause and from cardiovascular causes, associated with azithromycin were greater than those associated with amoxicillin. For every 21,000 outpatient prescriptions written for azithromycin, one cardiovascular death occurred in excess of those observed with the same number of amoxicillin prescriptions. The excess risk over amoxicillin varied considerably according to cardiovascular risk factors; the researchers estimated that there was one excess cardiovascular death per 4100 prescriptions among patients at high cardiovascular risk but less than one per 100,000 among patients with lower cardiovascular risk.

The study by Ray et al. has limitations that are intrinsic to observational, nonrandomized clinical studies. In particular, nonrandomized studies cannot exclude the possibility that patients receiving a drug under evaluation differ from control patients in some important but undetected way, causing bias in the results. Such confounding may bias comparisons not only between patients receiving antibacterial drugs and those receiving no antibacterials but also between patients receiving different antibacterials. Although Ray et al. used appropriate analytic methods to address potential confounding, we cannot know for certain whether these methods were fully successful. Replication of the authors’ results, through analysis of a distinct data set, would provide more confidence in the finding of increased cardiovascular mortality among patients receiving azithromycin.

Despite such caveats, the results presented by Ray et al. warrant serious attention. A chief strength of the results is the time-limited pattern of the risk: the azithromycin-associated increase in the rates of death from any cause and from cardiovascular causes spanned days 1 through 5, reflecting the typical 5-day duration of azithromycin administration (e.g., Zithromax Z-Pak). On days 6 through 10, an elevated risk of death from cardiovascular causes was no longer detected. This pattern is consistent with the timing of peak plasma azithromycin concentrations and the concomitant risk of QT-interval prolongation. The elevated risk was statistically significant, regardless of whether azithromycin treatment was compared with amoxicillin or with nonuse of an antibacterial drug. Furthermore, the observed excess mortality was attributable solely to cardiovascular deaths and, in particular, to sudden cardiac death; although sudden cardiac death can result from causes other than arrhythmias, an increase in deaths in this category would be the pattern expected from an arrhythmogenic, QT-interval–prolonging drug. Also, the azithromycin-associated risk was higher among patients with cardiovascular disorders, which is consistent with a drug-related arrhythmia.

A new study by Svanström and colleagues (pages 1704–1712), using Danish national health care data, found no difference between azithromycin and penicillin V in the 5-day risk of cardiovascular death (relative risk, 0.93; 95% confidence interval [CI], 0.56 to 1.55). However, the upper bound of the 95% confidence interval does not exclude an increased risk of as much as 55%. As Svanström et al. point out, the population they studied differed from that studied by Ray et al. with respect to the baseline risk of death and cardiovascular risk factors. Overall, the Danish patients had better cardiovascular health than the Tennessee Medicaid patients. In a subgroup analysis of patients with a history of cardiovascular disease, the risk ratio for azithromycin versus penicillin V was greater than 1, though the difference was not statistically significant (relative risk, 1.35; 95% CI, 0.69 to 2.64). Svanström et al. conclude that their results do not conflict with those of Ray et al. Rather, the effect on cardiovascular mortality may be limited to patients with cardiovascular disease.

One must, of course, weigh any observed drug-associated risk against clinical benefits, so it’s appropriate to consider the possibility that certain offsetting benefits of azithromycin may not have been reflected in the risk data analyzed by Ray et al. For example, other studies have suggested that macrolides have an advantage over other antibacterial agents in terms of overall survival from community-acquired pneumonia. In a recent Canadian observational study, researchers followed 2973 outpatients with community-acquired pneumonia and found significantly lower 30-day mortality among patients receiving macrolides than among those receiving fluoroquinolones (adjusted odds ratio, 0.28; 95% CI, 0.09 to 0.86).2 A recent meta-analysis of observational studies showed a statistically significant 25% difference in mortality among hospitalized patients with community-acquired pneumonia favoring macrolides over nonmacrolide antibacterials.3 Such findings, which must be considered with due regard for the limits of observational studies, do not necessarily contradict the results of Ray et al. Past the 5-day period of risk of azithromycin-associated cardiovascular death, the drug might reduce the longer-term (e.g., more-than-30-day) rate of death due to pneumonia. Pneumonia was an uncommon indication among the Tennessee Medicaid patients treated with azithromycin.

Clinicians must consider the arrhythmogenic potential not only of azithromycin but also of potential alternative antibacterial drugs. An earlier study showed an association between the use of erythromycin and sudden cardiac death, augmented by concomitant use of inhibitors of the cytochrome P-450 3A isozymes that metabolize erythromycin.4 Labels for erythromycin and clarithromycin include warnings regarding QT-interval prolongation and arrhythmias. All labels for fluoroquinolone products similarly have warnings regarding QT-interval prolongation, and grepafloxacin was withdrawn from the market because of that risk. A recent observational study of elderly residents of Quebec, Canada, showed an association between outpatient fluoroquinolone use and serious arrhythmias (as defined by hospital discharge diagnoses of ventricular arrhythmia or sudden or unattended death).5 And although Ray et al. found the risk of cardiovascular death to be greater with azithromycin than with ciprofloxacin, they found the risk with levofloxacin similar to that with azithromycin. The authors interpreted this similarity as evidence that levofloxacin may be proarrhythmic; however, levofloxacin was not implicated as proarrhythmic in the Canadian study.

We investigated the most common ambulatory indications for azithromycin by analyzing data from a survey conducted by Encuity Research of approximately 3200 office-based physicians for the decade from 2002 through 2011. Across all age groups of patients, the two most common indications for azithromycin were chronic sinusitis and bronchitis.

Azithromycin was the leading antibacterial drug for outpatient treatment of bronchitis during this period (even if amoxicillin is combined with amoxicillin–clavulanate). For chronic sinusitis, azithromycin ranked second after amoxicillin. Because the indications are reported by the prescribing physicians, these data don’t allow us to assess the diagnostic certainty regarding the infections being treated.

The risks and benefits of antibacterial therapy should be considered in prescribing decisions. Pharmacologic and epidemiologic data point to lethal arrhythmias as a potential consequence of QT-interval prolongation with use of azithromycin, other macrolides, and fluoroquinolones. This possibility should give clinicians pause when they’re considering prescribing antibacterial drugs, especially for patients with preexisting cardiovascular risk factors or clinical conditions in which antibacterial drug therapy has limited benefits.

Source: NEJM