Adrian Root

Cardiovascular outcomes associated with use of clarithromycin: population based study

Study question What is the association between clarithromycin use and cardiovascular outcomes? Methods In this population based study the authors compared cardiovascular outcomes in adults aged 18 or more receiving oral clarithromycin or amoxicillin during 2005-09 in Hong Kong. Based on age within five years, sex, and calendar year at use, each clarithromycin user was matched to one or two amoxicillin users. The cohort analysis included patients who received clarithromycin (n=108 988) or amoxicillin (n=217 793). The self controlled case series and case crossover analysis included those who received Helicobacter pylori eradication treatment containing clarithromycin. The primary outcome was myocardial infarction. Secondary outcomes were all cause, cardiac, or non-cardiac mortality, arrhythmia, and stroke. Study answer and limitations The propensity score adjusted rate ratio of myocardial infarction 14 days after the start of antibiotic treatment was 3.66 (95% confidence interval 2.82 to 4.76) comparing clarithromycin use (132 events, rate 44.4 per 1000 person years) with amoxicillin use (149 events, 19.2 per 1000 person years), but no long term increased risk was observed. Similarly, rate ratios of secondary outcomes increased significantly only with current use of clarithromycin versus amoxicillin, except for stroke. In the self controlled case analysis, there was an association between current use of H pylori eradication treatment containing clarithromycin and cardiovascular events. The risk returned to baseline after treatment had ended. The case crossover analysis also showed an increased risk of cardiovascular events during current use of H pylori eradication treatment containing clarithromycin. The adjusted absolute risk difference for current use of clarithromycin versus amoxicillin was 1.90 excess myocardial infarction events (95% confidence interval 1.30 to 2.68) per 1000 patients. What this study adds Current use of clarithromycin was associated with an increased risk of myocardial infarction, arrhythmia, and cardiac mortality short term but no association with long term cardiovascular risks among the Hong Kong population. Funding, competing interests, data sharing ID was funded by grants from the Medical Research Council for this project. LS was funded by a grant from the Wellcome Trust. The authors have no competing interests. No additional data are available.

Association between oral fluoroquinolones and seizures: A self-controlled case series study.

Objectives: The aim of this study was to investigate the association and to estimate the crude absolute risk of seizure among patients exposed to fluoroquinolones (FQs) in Hong Kong and the United Kingdom. Methods: A self-controlled case series study was conducted. Data were collected from the Hong Kong Clinical Data Analysis and Reporting System database and the Clinical Practice Research Datalink. Patients who were prescribed any oral FQ and had an incident seizure diagnosis from 2001 to 2013 were included. The risk windows were defined as pre-FQ start, FQ-exposed, and post-FQ completion. Incidence rate ratios were estimated in all risk windows and compared with baseline periods. A post hoc subgroup analysis was conducted to examine the effect of patients with a history of seizure. Results: An increased incidence rate ratio was found in the pre-FQ start periods and no association was found in the post-FQ completion periods in both databases. The crude absolute risk of an incident seizure in 10,000 oral FQ prescriptions was 0.72 (95% confidence interval 0.47–1.10) in the Clinical Data Analysis and Reporting System and 0.40 (95% confidence interval 0.30–0.54) in the Clinical Practice Research Datalink. The rate ratio during treatment was not higher than pre-FQ start periods among patients with a history of seizure, therefore the results did not raise serious concerns. Conclusions: This study does not support a causal association between the use of oral FQs and the subsequent occurrence of seizure. An increased risk before the FQ exposure period suggests that the clinical indication for which FQ was prescribed may have contributed to the development of seizure rather than the drug itself.

Evaluation of the risk of cardiovascular events with clarithromycin using both propensity score and self-controlled study designs.

Abstract Aim Some previous studies suggest a long term association between clarithromycin use and cardiovascular events. This study investigates this association for clarithromycin given as part of Helicobacter pylori treatment (HPT). Methods Our source population was the Clinical Practice Research Datalink (CPRD), a UK primary care database. We conducted a self‐controlled case series (SCCS), a case–time–control study (CTC) and a propensity score adjusted cohort study comparing the rate of cardiovascular events in the 3 years after exposure to HPT containing clarithromycin with exposure to clarithromycin free HPT. Outcomes were first incident diagnosis of myocardial infarction (MI), arrhythmia and stroke. For the cohort analysis we included secondary outcomes all cause and cardiovascular mortality. Results Twenty‐eight thousand five hundred and fifty‐two patients were included in the cohort. The incidence rate ratio of first MI within 1 year of exposure to HPT containing clarithromycin was 1.07 (95% CI 0.85, 1.34, P = 0.58) and within 90 days was 1.43 (95% CI 0.99, 2.09 P = 0.057) in the SCCS analysis. CTC and cohort results were consistent with these findings. Conclusions There was some evidence for a short term association for first MI but none for a long term association for any outcome.

Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study

Abstract Objective To determine if trimethoprim use for urinary tract infection (UTI) is associated with an increased risk of acute kidney injury, hyperkalaemia, or sudden death in the general population. Design Cohort study. Setting UK electronic primary care records from practices contributing to the Clinical Practice Research Datalink linked to the Hospital Episode Statistics database. Participants Adults aged 65 and over with a prescription for trimethoprim, amoxicillin, cefalexin, ciprofloxacin, or nitrofurantoin prescribed up to three days after a primary care diagnosis of UTI between April 1997 and September 2015. Main outcome measures The outcomes were acute kidney injury, hyperkalaemia, and death within 14 days of a UTI treated with antibiotics. Results Among a cohort of 1 191 905 patients aged 65 and over, 178 238 individuals were identified with at least one UTI treated with antibiotics, comprising a total of 422 514 episodes of UTIs treated with antibiotics. The odds of acute kidney injury in the 14 days following antibiotic initiation were higher following trimethoprim (adjusted odds ratio 1.72, 95% confidence interval 1.31 to 2.24) and ciprofloxacin (1.48, 1.03 to 2.13) compared with amoxicillin. The odds of hyperkalaemia in the 14 days following antibiotic initiation were only higher following trimethoprim (2.27, 1.49 to 3.45) compared with amoxicillin. However, the odds of death within the 14 days following antibiotic initiation were not higher with trimethoprim than with amoxicillin: in the whole population the adjusted odds ratio was 0.90 (95% confidence interval 0.76 to 1.07) while among users of renin-angiotensin system blockers the odds of death within 14 days of antibiotic initiation was 1.12 (0.80 to 1.57). The results suggest that, for 1000 UTIs treated with antibiotics among people 65 and over, treatment with trimethoprim instead of amoxicillin would result in one to two additional cases of hyperkalaemia and two admissions with acute kidney injury, regardless of renin-angiotensin system blockade. However, for people taking renin-angiotensin system blockers and spironolactone treatment with trimethoprim instead of amoxicillin there were 18 additional cases of hyperkalaemia and 11 admissions with acute kidney injury. Conclusion Trimethoprim is associated with a greater risk of acute kidney injury and hyperkalaemia compared with other antibiotics used to treat UTIs, but not a greater risk of death. The relative risk increase is similar across population groups, but the higher baseline risk among those taking renin-angiotensin system blockers and potassium-sparing diuretics translates into higher absolute risks of acute kidney injury and hyperkalaemia in these groups.

Comparative effectiveness of fourth-line anti-hypertensive agents in resistant hypertension: A systematic review and meta-analysis

Aim We assessed the effectiveness of fourth-line mineralocorticoid receptor antagonists in comparison with other fourth-line anti-hypertensive agents in resistant hypertension. Methods and results We systematically searched Medline, EMBASE and the Cochrane library from database inception until January 2016. We included randomised and non-randomised studies that compared mineralocorticoid receptor antagonists with other fourth-line anti-hypertensive agents in patients with resistant hypertension. The outcome was change in systolic blood pressure, measured in the office, at home or by ambulatory blood pressure monitoring. Secondary outcomes were changes in serum potassium and occurrence of hyperkalaemia. We used random effects models and assessed statistical heterogeneity using the I2 test and corresponding 95% confidence intervals. From 2,506 records, 5 studies met our inclusion criteria with 755 included patients. Two studies were randomised and three were non-randomised. Comparative fourth-line agents included bisoprolol, doxazosin, furosemide and additional blockade of the renin angiotensin-aldosterone system. Using data from randomised studies, mineralocorticoid receptor antagonists reduced blood pressure by 7.4 mmHg (95%CI 3.2 – 11.6) more than the active comparator. When limited to non-randomised studies, mineralocorticoid receptor antagonists reduced blood pressure by 11.9 mmHg (95% CI 9.3 – 14.4) more than the active comparator. Conclusion On the basis of this meta-analysis, mineralocorticoid receptor antagonists reduce blood pressure more effectively than other fourth-line agents in resistant hypertension. Effectiveness stratified by ethnicity and comorbidities, in addition to information on clinical outcomes such as myocardial infarction and stroke, now needs to be determined.

Cardiovascular Outcomes Following a Respiratory Tract Infection among Adults with Non-CF Bronchiectasis: A General Population Based Study.

Rationale: Studies suggest that adults with bronchiectasis are at increased risk of cardiovascular comorbidities. Objectives: We aimed to quantify the relative risk of incident cardiovascular events after a respiratory tract infection among adults with bronchiectasis. Methods: Using UK electronic primary care records, we conducted a within‐person comparison using the self‐controlled case series method. We calculated the relative risk of first‐time cardiovascular events (either first myocardial infarction or stroke) after a respiratory tract infection compared with the individuals baseline risk. Results: Our cohort consisted of 895 adult men and women with non‐cystic fibrosis bronchiectasis with a first myocardial infarction or stroke and at least one respiratory tract infection. There was an increased rate of first‐time cardiovascular events in the 91‐day period after a respiratory tract infection (incidence rate ratio, 1.56; 95% confidence interval, 1.20‐2.02). The rate of a first cardiovascular event was highest in the first 3 days after a respiratory tract infection (incidence rate ratio, 2.73; 95% confidence interval, 1.41‐5.27). Conclusions: These data suggest that respiratory tract infections are strongly associated with a transient increased risk of first‐time myocardial infarction or stroke among people with bronchiectasis. As respiratory tract infections are six times more common in people with bronchiectasis than the general population, the increased risk has a disproportionately greater impact in these individuals. These findings may have implications for including cardiovascular risk modifications in airway infection treatment pathways in this population.

Quantification of the risk of liver injury associated with flucloxacillin : a UK population-based cohort study

Background: Flucloxacillin is an established cause of liver injury. Despite this, there are a lack of published data on both the strength of association after adjusting for potential confounders, and the absolute incidence among different subgroups of patients. Objectives: To assess the relative and absolute risks of liver injury following exposure to flucloxacillin and identify subgroups at potentially increased risk. Methods: A cohort study between 1 January 2000 and 1 January 2012 using the UK Clinical Practice Research Datalink, including 1046699 people with a first prescription for flucloxacillin (861962) or oxytetracycline (184737). Absolute risks of experiencing both symptom‐defined (jaundice) and laboratory‐confirmed liver injury within 1–45 and 46–90 days of antibiotic initiation were estimated. Multivariable logistic regression was used to estimate 1–45 day relative effects. Results: There were 183 symptom‐defined cases (160 prescribed flucloxacillin) and 108 laboratory‐confirmed cases (102 flucloxacillin). The 1–45 day adjusted risk ratio for laboratory‐confirmed injury was 5.22 (95% CI 1.64–16.62) comparing flucloxacillin with oxytetracycline use. The 1–45 day risk of laboratory‐confirmed liver injury was 8.47 per 100000 people prescribed flucloxacillin (95% CI 6.64–10.65). People who received consecutive flucloxacillin prescriptions had a 1–45 day risk of jaundice of 39.00 per 100000 (95% CI 26.85–54.77), while those aged >70 receiving consecutive prescriptions had a risk of 110.57 per 100000 (95% CI 70.86–164.48). Conclusions: The short‐term risk of laboratory‐confirmed liver injury was >5‐fold higher after a flucloxacillin prescription than an oxytetracycline prescription. The risk of flucloxacillin‐induced liver injury is particularly high within those aged >70 and those who receive multiple flucloxacillin prescriptions. The stratified risk estimates from this study could help guide clinical care.

NNTs and NNHs: handle with care

Best medical practice should be informed by research evidence. However, translating study findings into clinical decisions is not straightforward. Ratio measures of effect such as the risk ratio are most commonly reported, but tell us little about absolute effects. For example, taking a statin reduces your risk of vascular events by about 20% a year across a wide range of baseline vascular risk.1 If your initial 10-year risk of such an event was 1% then taking a statin would reduce this risk by 0.2%, whereas if your initial risk was 20%, the reduction would be 4%. This shows how the absolute risk difference can be more clinically informative. The number needed to treat (NNT) statistic was introduced over 30 years ago and has gained popularity as a useful measure to help clinicians understand research findings.2 Abstract probabilities are converted into a more tangible quantity: number of patients treated. In the above statins example, the NNT for 10 years to avert one vascular event would be …

OS 04-07 THE COMPARATIVE EFFECTIVENESS OF 4TH LINE ANTI-HYPERTENSIVE AGENTS IN PATIENTS WITH RESISTANT HYPERTENSION: A META-ANALYSIS.

Objective: Recent evidence points to the effectiveness of spironolactone vs placebo in the treatment of resistant hypertension (RH). However, placebo is rarely a realistic treatment choice in uncontrolled hypertension. Using meta-analysis, we assessed the effectiveness of alternative 4th line anti-hypertensive agents in comparison to 4th line spironolactone/eplenerone in RH. Design and Method: Pubmed, EMBASE and the Cochrane library were systematically searched for randomised and non-randomised studies that compared any 4th line anti-hypertensive agent to spironolactone/eplenerone in RH. Data extraction and quality appraisal were carried out in duplicate. The outcome was change in systolic BP, measured in the office, at home or by ambulatory blood pressure monitoring (AMBP). A random effects model was used to pool the data. Statistical heterogeneity was assessed using the I2 test. Sensitivity analyses were carried out according to study design and method of BP measurement. Results: From 2,506 records, we identified 1 RCT and 5 observational studies according to our inclusion criteria with 877 included patients (Table 1). The mean age was 57.3yrs, 29.5% female, 41.4% diabetic, mean eGFR of 83.7 ml/min and mean BMI of 29.8 kg/m2. The baseline systolic BP was 143.1 mmHg. Other 4th line agents included bisoprolol, doxazosin and furosemide. When all the data was pooled, spironolactone reduced systolic BP by -10.19mmHg (95% CI 6.76 – 13.62) (Figure 1) more than the active comparator. When limited to studies that measured 24hr AMBP, spironolactone reduced BP by 9.99mmHg (95% CI 7.14 – 12.84) relative to the comparator. Analysing observational studies only, spironolactone reduced systolic BP by 11.24mmHg (95% CI 8.04 – 14.43). Conclusions: On the basis of this meta-analysis, spironolactone reduces systolic BP more effectively than other potential 4th line treatment options in RH. The comparative effectiveness of 4th line agents with regard to clinical outcomes such as myocardial infarction and stroke now needs to be determined.