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1.  Risk of acute kidney injury associated with the use of fluoroquinolones 
Background:
Case reports indicate that the use of fluoroquinolones may lead to acute kidney injury. We studied the association between the use of oral fluoroquinolones and acute kidney injury, and we examined interaction with renin–angiotensin-system blockers.
Methods:
We formed a nested cohort of men aged 40–85 enrolled in the United States IMS LifeLink Health Plan Claims Database between 2001 and 2011. We defined cases as men admitted to hospital for acute kidney injury, and controls were admitted to hospital with a different presenting diagnosis. Using risk-set sampling, we matched 10 controls to each case based on hospital admission, calendar time (within 6 wk), cohort entrance (within 6 wk) and age (within 5 yr). We used conditional logistic regression to assess the rate ratio (RR) for acute kidney injury with current, recent and past use of fluoroquinolones, adjusted by potential confounding variables. We repeated this analysis with amoxicillin and azithromycin as controls. We used a case-time–control design for our secondary analysis.
Results:
We identified 1292 cases and 12 651 matched controls. Current fluoroquinolone use had a 2.18-fold (95% confidence interval [CI] 1.74–2.73) higher adjusted RR of acute kidney injury compared with no use. There was no association between acute kidney injury and recent (adjusted RR 0.87, 95% CI 0.66–1.16) or past (RR 0.86, 95% CI 0.66–1.12) use. The absolute increase in acute kidney injury was 6.5 events per 10 000 person-years. We observed 1 additional case per 1529 patients given fluoroquinolones or per 3287 prescriptions dispensed. The dual use of fluoroquinolones and renin–angiotensin-system blockers had an RR of 4.46 (95% CI 2.84–6.99) for acute kidney injury. Our case-time–control analysis confirmed an increased risk of acute kidney injury with fluoroquinolone use (RR 2.16, 95% CI 1.52–3.18). The use of amoxicillin or azithromycin was not associated with acute kidney injury.
Interpretation:
We found a small, but significant, increased risk of acute kidney injury among men with the use of oral fluoroquinolones, as well as a significant interaction between the concomitant use of fluoroquinolones and renin–angiotensin-system blockers.
doi:10.1503/cmaj.121730
PMCID: PMC3708027  PMID: 23734036
2.  Time Variability of C-Reactive Protein: Implications for Clinical Risk Stratification 
PLoS ONE  2013;8(4):e60759.
Background
C-reactive protein (CRP) is proposed as a screening test for predicting risk and guiding preventive approaches in coronary artery disease (CAD). However, the stability of repeated CRP measurements over time in subjects with and without CAD is not well defined. We sought to determine the stability of serial CRP measurements in stable subjects with distinct CAD manifestations and a group without CAD while carefully controlling for known confounders.
Methods
We prospectively studied 4 groups of 25 stable subjects each 1) a history of recurrent acute coronary events; 2) a single myocardial infarction ≥7 years ago; 3) longstanding CAD (≥7 years) that had never been unstable; 4) no CAD. Fifteen measurements of CRP were obtained to cover 21 time-points: 3 times during one day; 5 consecutive days; 4 consecutive weeks; 4 consecutive months; and every 3 months over the year. CRP risk threshold was set at 2.0 mg/L. We estimated variance across time-points using standard descriptive statistics and Bayesian hierarchical models.
Results
Median CRP values of the 4 groups and their pattern of variability did not differ substantially so all subjects were analyzed together. The median individual standard deviation (SD) CRP values within-day, within-week, between-weeks and between-months were 0.07, 0.19, 0.36 and 0.63 mg/L, respectively. Forty-six percent of subjects changed CRP risk category at least once and 21% had ≥4 weekly and monthly CRP values in both low and high-risk categories.
Conclusions
Considering its large intra-individual variability, it may be problematic to rely on CRP values for CAD risk prediction and therapeutic decision-making in individual subjects.
doi:10.1371/journal.pone.0060759
PMCID: PMC3620269  PMID: 23579782
3.  Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis 
Background:
There is an increased risk of venous thromboembolism among women taking oral contraceptives. However, whether there is an additional risk among women with polycystic ovary syndrome (PCOS) is unknown.
Methods:
We developed a population-based cohort from the IMS LifeLink Health Plan Claims Database, which includes managed care organizations in the United States. Women aged 18–46 years taking combined oral contraceptives and who had a claim for PCOS (n = 43 506) were matched, based on a propensity score, to control women (n = 43 506) taking oral contraceptives. Venous thromboembolism was defined using administrative coding and use of anticoagulation. We used Cox proportional hazards models to assess the relative risk (RR) of venous thromboembolism among users of combined oral contraceptives with and without PCOS.
Results:
The incidence of venous thromboembolism among women with PCOS was 23.7/10 000 person-years, while that for matched controls was 10.9/10 000 person-years. Women with PCOS taking combined oral contraceptives had an RR for venous thromboembolism of 2.14 (95% confidence interval [CI] 1.41–3.24) compared with other contraceptive users. The incidence of venous thromboembolism was 6.3/10 000 person-years among women with PCOS not taking oral contraceptives; the incidence was 4.1/10 000 person-years among matched controls. The RR of venous thromboembolism among women with PCOS not taking oral contraceptives was 1.55 (95% CI 1.10–2.19).
Interpretation:
We found a 2-fold increased risk of venous thromboembolism among women with PCOS who were taking combined oral contraceptives and a 1.5-fold increased risk among women with PCOS not taking oral contraceptives. Physicians should consider the increased risk of venous thromboembolism when prescribing contraceptive therapy to women with PCOS.
doi:10.1503/cmaj.120677
PMCID: PMC3563911  PMID: 23209115
4.  A meta-analysis of antibiotic use for the secondary prevention of cardiovascular diseases 
BACKGROUND:
A number of clinical trials have examined whether antibiotics decrease the incidence of adverse events in patients with cardiovascular diseases. However, results have occasionally been conflicting, and a meta-analysis may provide additional clarification.
OBJECTIVE:
To address whether antibiotic use can reduce the risk of future cardiac events among patients with established cardiovascular diseases.
METHODS:
PubMed and the Cochrane Central Register of Controlled Trials were searched using the key words “antibiotic” and “cardiovascular diseases”. Only randomized, placebo-controlled trials of patients with established cardiovascular disease and reporting cardiovascular outcomes were included. A random effects model was used and a fixed model was applied for sensitivity analysis.
RESULTS:
A total of 393 papers published between January 1, 1994, and April 31, 2006, were initially identified. Thirteen trials (12,491 patients in the treatment group and 12,518 patients in the control group) were retained and included in the present meta-analysis. The pooled RR for the composite event end point, including death, myocardial infarction admission and unplanned revascularization procedures, was 0.96 (95% CI 0.90 to 1.04). No associations were seen for the individual outcomes of mortality (RR 1.07, 95% CI 0.96 to 1.19) or myocardial infarction/unstable angina (RR 0.96, 95% CI 0.85 to 1.07). Subgroup analyses based on patient populations (stable or unstable), type of antibiotics, or restricted to those with immunoglobulin G Chlamydia pneumoniae antibodies were also negative for a beneficial treatment effect. Similar results were found using a fixed effects model.
CONCLUSIONS:
The meta-analysis did not provide evidence of an association between antibiotic use and the secondary prevention of cardiac events. Further research in this area does not appear to be promising.
PMCID: PMC2643142  PMID: 18464945
Antibiotic; Cardiovascular diseases; Meta-analysis; Secondary prevention
5.  Resource allocation among cardiovascular specialists and trainees: A pilot survey 
OBJECTIVE
To assess the relative importance that cardiovascular specialists assign to new technologies.
METHODS
A pilot survey of practising cardiologists in one tertiary hospital and cardiology trainees from two university programs. Respondents were asked to distribute a hypothetical budget among several new technologies.
RESULTS
A total of 28 responses (response rate of 62%) were analyzed. In the hypothetical situation described, doctors appeared willing to spend approximately equal amounts on implantable cardiac defibrillators (median 25%, interquartile range 5% to 30%) and bare metal coronary stents (median 28%, interquartile range 20% to 40%). Physicians were more restrained in their allocation for refinements of these two technologies, including drug-eluting stents and biventricular pacing. Wide individual variations in technology use were noted.
CONCLUSIONS
There is considerable uncertainty among cardiovascular specialists regarding the relative value of new technologies. Further work is required to better quantify this uncertainty and its determinants.
PMCID: PMC2644565  PMID: 18273484
Cardiovascular medicine; Health economics; Technology evaluation
7.  Statin wars following coronary revascularization –Evidence-based clinical practice? 
BACKGROUND
Randomized clinical trials (RCTs) have shown that statins provide substantial heath benefits. Pharmaceutical companies spend enormous amounts of money on both clinical trials and marketing. The relative influence of information from clinical trials on physician prescription patterns for statins is unknown.
OBJECTIVE
To examine the correlation between statin prescription patterns and the quality of evidence from RCTs.
METHODS
Using the computerized administrative databases of the Quebec Health Insurance Board, the choice of statin for elderly patients (older than 65 years of age) following a coronary revascularization procedure (percutaneous coronary intervention or coronary artery bypass graft surgery) performed between January 1, 1994, and June 30, 2003, was examined. Prescriptions for each statin were compared with their evidence base obtained from a cumulative systematic literature review of RCTs that recorded mortality as an outcome and were published before December 31, 2002.
RESULTS
The study cohort comprised 27,979 elderly revascularized patients who received at least one statin prescription. In 1996, the year atorvastatin was introduced, simvastatin and pravastatin had 38.3% and 37.1% of the market share, respectively. By 2003, atorvastatin had 44% of the market share, compared with 29.9% and 24.1% for simvastatin and pravastatin, respectively. In contrast, RCTs published up to the end of 2002 had culminated in 133,341 and 140,565 patient-years of follow-up for simvastatin and pravastatin, respectively, and only 1459 patient-years for atorvastatin.
CONCLUSIONS
Prescription patterns regarding the choice of statin do not appear to be determined uniquely from high-quality RCTs. Further research into the other possible determinants of physician prescription patterns is necessary.
PMCID: PMC2538985  PMID: 16450018
Cholesterol; Prescription patterns; Secondary prevention; Statins
8.  The association between drospirenone and hyperkalemia: a comparative-safety study 
Background
Drospirenone/ethinyl-estradiol is an oral contraceptive (OC) that possesses unique antimineralocorticoid activity. It is conjectured that drospirenone, taken alone or concomitantly with spironolactone, may be associated with an increased risk of hyperkalemia.
Methods
A retrospective cohort study was conducted evaluating women between 18-46 years of age in the Lifelink™ Health Plan Claims Database. The study was restricted to new users of OCs between 1997-2009. Cox proportional hazards models were used to estimate the time to first occurrence of hyperkalemia diagnosis. The main analysis compared OCs containing drospirenone with OCs containing levonorgestrel, a second generation OC not known to impact potassium homeostasis. Logistic regression evaluated concomitant prescribing of drospirenone and spironolactone
Results
The cohort included 1,148,183 women, averaging 28.8 years of age and 280 days of OC therapy. 2325 cases of hyperkalemia were identified. The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95-1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy.
Conclusions
A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert.
doi:10.1186/1472-6904-11-23
PMCID: PMC3265420  PMID: 22208934
9.  Routine invasive management after fibrinolysis in patients with ST-elevation myocardial infarction: a systematic review of randomized clinical trials 
Background
Patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolysis are increasingly, and ever earlier, referred for routine coronary angiography and where feasible, undergo percutaneous coronary intervention (PCI). We sought to examine the randomized clinical trials (RCTs) on which this approach is based.
Methods
We systematically searched EMBASE, Medline, and references of relevant studies. All contemporary RCTs (published since 1995) that compared systematic invasive management of STEMI patients after fibrinolysis with standard care were included. Relevant study design and clinical outcome data were extracted.
Results
Nine RCTs that randomized a total of 3320 patients were identified. All suggested a benefit from routine early invasive management. They were individually reviewed but important design variations precluded a formal quantitative meta-analysis. Importantly, several trials did not compare a routine practice of invasive management after fibrinolysis with a more selective 'ischemia-guided' approach but rather compared an early versus later routine invasive strategy. In the other studies, recourse to subsequent invasive management in the usual care group varied widely. Comparison of the effectiveness of a routine invasive approach to usual care was also limited by asymmetric use of a second anti-platelet agent, differing enzyme definitions of reinfarction occurring spontaneously versus as a complication of PCI, a preponderance of the 'soft' outcome of recurrent ischemia in the combined primary endpoint, and an interpretative bias when invasive procedures on follow-up were tallied as an endpoint without considering initial invasive procedures performed in the routine invasive arm.
Conclusions
Due to important methodological limitations, definitive RCT evidence in favor of routine invasive management following fibrinolysis in patients with STEMI is presently lacking.
doi:10.1186/1471-2261-11-34
PMCID: PMC3145591  PMID: 21689449
10.  The disutility of restenosis – the impact of repeat percutaneous coronary intervention on quality of life 
The Canadian Journal of Cardiology  2010;26(6):e197-e200.
BACKGROUND:
Percutaneous coronary intervention (PCI) with coronary stenting is a common medical procedure that is used to treat the symptoms of both stable angina and acute coronary syndromes. Drug-eluting stents (DES) decrease restenosis and repeat revascularization procedures but are more expensive than bare-metal stents. A proper cost-effectiveness analysis of DES requires an understanding of the health value patients place on the avoidance of restenosis accompanied by a repeat PCI.
OBJECTIVE:
To estimate quality-of-life (QoL) benefits ascribed to avoiding the return of coronary symptoms and the need for a repeat revascularization procedure.
METHODS:
A prospective, single-centre study was conducted involving PCI patients. A time trade-off (TTO) question, based on a hypothetical restricted lifespan of 10 years, was used to estimate the QoL benefits patients attach to the avoidance of recurrent symptoms and a repeat PCI. This was accomplished by interviewing the patients by telephone, two weeks post-PCI. The TTO question was also administered to the catheterization laboratory staff.
RESULTS:
Between January and March 2007, and between April and June 2008, 103 interviews were completed. The median TTO was zero weeks (interquartile range zero to 1.7 weeks). Six interventional cardiologists and eight cardiac catheterization nurses reported a similar median disutility.
CONCLUSION:
Despite acknowledgement of the substantial clinical benefits of DES, the results of the present study suggest that patients do not place a great disutility on avoiding restenosis, thereby providing little QoL justification for the large incremental cost associated with this technology.
PMCID: PMC2903991  PMID: 20548981
Angioplasty; Quality of life; Restenosis
11.  Oral contraceptives and the risk of gallbladder disease: a comparative safety study 
Background
Recent concerns have been raised about the risk of gallbladder disease associated with the use of drospirenone, a fourth-generation progestin used in oral contraceptives. We conducted a study to determine the magnitude of this risk compared with other formulations of oral contraceptives.
Methods
We conducted a retrospective cohort study using the IMS LifeLink Health Plan Claims Database. We included women who were using an oral contraceptive containing ethinyl estradiol combined with a progestin during 1997–2009. To be eligible, women had to have been taking the oral contraceptive continuously for at least six months. We computed adjusted rate ratios (RRs) for gallbladder disease using a Cox proportional hazards model. In the primary analysis, gallbladder disease was defined as cholecystectomy; in a secondary analysis, it was defined as hospital admission secondary to gallbladder disease.
Results
We included 2 721 014 women in the cohort, 27 087 of whom underwent surgical or laparoscopic cholecystectomy during the follow-up period. Compared with levonorgestrel, an older second-generation progestin, a small, statistically significant increase in the risk of gallbladder disease was associated with desogestrel (adjusted RR 1.05, 95% confidence interval [CI] 1.01–1.09), drospirenone (adjusted RR 1.20, 95% CI 1.16–1.26) and norethindrone (adjusted RR 1.10, 95% CI 1.06–1.14). No statistically significant increase in risk was associated with the other formulations of oral contraceptive (ethynodiol diacetate, norgestrel and norgestimate).
Interpretation
In a large cohort of women using oral contraceptives, we found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethindrone compared with levonorgestrel. However, the small effect sizes compounded with the possibility of residual biases in this observational study make it unlikely that these differences are clinically significant.
doi:10.1503/cmaj.110161
PMCID: PMC3091897  PMID: 21502354
12.  The potential interaction between clopidogrel and proton pump inhibitors: a systematic review 
BMC Medicine  2010;8:81.
Background
Recently, several publications have investigated a possible drug interaction between clopidogrel and proton pump inhibitors (PPIs), and regulatory agencies have issued warnings despite discordant study results. In an attempt to clarify the situation, we performed a systematic review with a critical analysis of study methodologies to determine whether varying study quality (that is, bias) could explain the discordant results.
Methods
A systematic review of all studies reporting clinical outcomes was performed using an electronic literature search of the MEDLINE and EMBASE databases, abstracts from the major cardiology conferences and a hand-search of bibliographies from identified articles. Each study was evaluated for its risk of bias according to a prespecified quality measure scale.
Results
A total of 18 studies were identified. Ten of 13 studies judged to be of low scientific quality reported a statistically positive interaction between clopidogrel and the general class of PPIs, and each concluded this was likely a clinically meaningful effect. None of the five studies judged to be of moderate or high quality reported a statistically significant association. Multiple sources of heterogeneity (that is, different populations, outcomes assessed, drug exposure methods and study quality) prevented a formal quantitative analysis of all studies. An increased risk of bias was observed in the positive studies, resulting in an inverse correlation between study quality and a reported statistically positive interaction (10/13 versus 0/5; P = p = 0.007). There was also no clinical evidence for a positive interaction according to specific PPIs.
Conclusion
The observed association between clopidogrel and PPIs is found uniquely in studies judged to be of low quality and with an increased risk of bias. High-quality evidence supporting a clinically significant clopidogrel/PPI interaction is presently lacking.
doi:10.1186/1741-7015-8-81
PMCID: PMC3016262  PMID: 21134261
13.  Has thrombolysis lost its mojo? 
Heart  2007;93(10):1167-1169.
See article on page 1244
doi:10.1136/hrt.2006.113878
PMCID: PMC2000951  PMID: 17890687
acute myocardial infarction; epidemiology; primary angioplasty; thrombolysis
14.  Omega-3 fatty acids in high-risk cardiovascular patients: a meta-analysis of randomized controlled trials 
Background
Multiple randomized controlled trials (RCTs) have examined the cardiovascular effects of omega-3 fatty acids and have provided unexplained conflicting results. A meta-analysis of these RCTs to estimate efficacy and safety and potential sources of heterogeneity may be helpful.
Methods
The Cochrane library, MEDLINE, and EMBASE were systematically searched to identify all interventional trials of omega-3 fatty acids compared to placebo or usual diet in high-risk cardiovascular patients. The primary outcome was all-cause mortality and secondary outcomes were coronary restenosis following percutaneous coronary intervention and safety. Meta-analyses were carried out using Bayesian random-effects models, and heterogeneity was examined using meta-regression.
Results
A total of 29 RCTs (n = 35,144) met our inclusion criteria, with 25 reporting mortality and 14 reporting restenosis. Omega-3 fatty acids were not associated with a statistically significant decreased mortality (relative risk [RR] = 0.88, 95% Credible Interval [CrI] = 0.64, 1.03) or with restenosis prevention (RR = 0.89, 95% CrI = 0.72, 1.06), though the probability of some benefit remains high (0.93 and 0.90, respectively). However in meta-regressions, there was a >90% probability that larger studies and those with longer follow-up were associated with smaller benefits. No serious safety issues were identified.
Conclusions
Although not reaching conventional statistical significance, the evidence to date suggests that omega-3 fatty acids may result in a modest reduction in mortality and restenosis. However, caution must be exercised in interpreting these benefits as results were attenuated in higher quality studies, suggesting that bias may be at least partially responsible. Additional high quality studies are required to clarify the role of omega-3 fatty acid supplementation for the secondary prevention of cardiovascular disease.
doi:10.1186/1471-2261-10-24
PMCID: PMC2894745  PMID: 20525225
15.  Microvolt T-wave alternans as a predictor of mortality and severe arrhythmias in patients with left-ventricular dysfunction: a systematic review and meta-analysis 
Background
Studies have demonstrated that the use of implantable cardioverter defibrillators (ICDs) is effective for the primary prevention of arrhythmic events but due to imposing costs, there remains a need to identify which patients will derive the greatest benefit. Microvolt T-wave alternans (MTWA) has been proposed to assist in this stratification.
Methods
We systematically searched the literature using MEDLINE, EMBASE, Current Contents, the Cochrane Library, INAHTA, and the Web of Science to identify all primary prevention randomized controlled trials and prospective cohort studies with at least 12 months of follow-up examining MTWA as a predictor of mortality and severe arrhythmic events in patients with severe left-ventricular dysfunction. The search was limited to full-text English publications between January 1990 and May 2007. The primary outcome was a composite of mortality and severe arrhythmias. Data were synthesized using Bayesian hierarchical models.
Results
We identified no trials and 8 published cohort studies involving a total of 1,946 patients, including 332 positive, 656 negative, 84 indeterminate, and 874 non-negative (which includes both positive and indeterminate tests) MTWA test results. The risk of mortality or severe arrhythmic events was higher in patients with a positive MTWA compared to a negative test (RR = 2.7, 95% credible interval (CrI) = 1.4, 6.1). Similar results were obtained when comparing non-negative MTWA to a negative test.
Conclusion
A positive MTWA test predicts mortality or severe arrhythmic events in a population of individuals with severe left ventricular dysfunction. However, the wide credible interval suggests the clinical utility of this test remains incompletely defined, ranging from very modest to substantial. Additional high quality studies are required to better refine the role of MTWA in the decision making process for ICD implantation.
doi:10.1186/1471-2261-9-5
PMCID: PMC2653469  PMID: 19175926
16.  The interpretation of systematic reviews with meta-analyses: an objective or subjective process? 
Background
Discrepancies between the conclusions of different meta-analyses (quantitative syntheses of systematic reviews) are often ascribed to methodological differences. The objective of this study was to determine the discordance in interpretations when meta-analysts are presented with identical data.
Methods
We searched the literature for all randomized clinical trials (RCT) and review articles on the efficacy of intravenous magnesium in the early post-myocardial infarction period. We organized the articles chronologically and grouped them in packages. The first package included the first RCT, and a summary of the review articles published prior to first RCT. The second package contained the second and third RCT, a meta-analysis based on the data, and a summary of all review articles published prior to the third RCT. Similar packages were created for the 5th RCT, 10th RCT, 20th RCT and 23rd RCT (all articles). We presented the packages one at a time to eight different reviewers and asked them to answer three clinical questions after each package based solely on the information provided. The clinical questions included whether 1) they believed magnesium is now proven beneficial, 2) they believed magnesium will eventually be proven to be beneficial, and 3) they would recommend its use at this time.
Results
There was considerable disagreement among the reviewers for each package, and for each question. The discrepancies increased when the heterogeneity of the data increased. In addition, some reviewers became more sceptical of the effectiveness of magnesium over time, and some reviewers became less sceptical.
Conclusion
The interpretation of the results of systematic reviews with meta-analyses includes a subjective component that can lead to discordant conclusions that are independent of the methodology used to obtain or analyse the data.
doi:10.1186/1472-6947-8-19
PMCID: PMC2408567  PMID: 18495019
18.  Lifestyle variables and the risk of myocardial infarction in the General Practice Research Database 
Background
The primary objective of this study is to estimate the association between body mass index (BMI) and the risk of first acute myocardial infarction (AMI). As a secondary objective, we considered the association between other lifestyle variables, smoking and heavy alcohol use, and AMI risk.
Methods
This study was conducted in the general practice research database (GPRD) which is a database based on general practitioner records and is a representative sample of the United Kingdom population. We matched cases of first AMI as identified by diagnostic codes with up to 10 controls between January 1st, 2001 and December 31st, 2005 using incidence density sampling. We used multiple imputation to account for missing data.
Results
We identified 19,353 cases of first AMI which were matched on index date, GPRD practice and age to 192,821 controls. There was a modest amount of missing data in the database, and the patients with missing data had different risks than those with recorded values. We adjusted our analysis for each lifestyle variable jointly and also for age, sex, and number of hospitalizations in the past year. Although a record of underweight (BMI <18.0 kg/m2) did not alter the risk for AMI (adjusted odds ratio (OR): 1.00; 95% confidence interval (CI): 0.87–1.11) when compared with normal BMI (18.0–24.9 kg/m2), obesity (BMI ≥30 kg/m2) predicted an increased risk (adjusted OR: 1.41; 95% CI: 1.35–1.47). A history of smoking also predicted an increased risk of AMI (adjusted OR: 1.81; 95% CI: 1.75–1.87) as did heavy alcohol use (adjusted OR: 1.15; 95% CI: 1.06–1.26).
Conclusion
This study illustrates that obesity, smoking and heavy alcohol use, as recorded during routine care by a general practitioner, are important predictors of an increased risk of a first AMI. In contrast, low BMI does not increase the risk of a first AMI.
doi:10.1186/1471-2261-7-38
PMCID: PMC2241637  PMID: 18088433
19.  Vaccination against human papillomavirus 
doi:10.1503/cmaj.1070128
PMCID: PMC2096515  PMID: 18056602
20.  Validity of electron beam computed tomography for coronary artery disease: asystematic review and meta-analysis 
BMC Medicine  2007;5:35.
Background
Electron beam computed tomography (EBCT) is a method for measuring coronary calcification and has been promoted as a possible non-invasive screening/diagnostic tool for coronary artery disease (CAD). Our objective was to carry out a systematic review and meta-analysis of EBCT for the screening of asymptomatic patients and the diagnosis of symptomatic patients for CAD.
Methods
Studies were identified from the PUBMED, MEDLINE, EMBASE, Current Contents, INAHTA and Cochrane Collaboration databases. We identified studies published in English evaluating EBCT using: (1) a prospective design among asymptomatic patients where CAD was measured in terms of clinical outcomes (e.g. myocardial infarction, death, revascularization); and (2)a cross-sectional design among symptomatic patients where CAD was measured by coronary angiography. We compared the risk of CAD in EBCT score categories defined as low (0–10), moderate (11–400) and high (>400). A hierarchical meta-analysis was used to pool risk ratios comparing categories across studies.
Results
We identified 9 studies of asymptomatic patients and 10 studies of symptomatic patients. In both types of studies, we found variability in EBCT category distribution and risk of CAD within categories. For studies of asymptomatic patients we estimated the following risk ratios (95% credible intervals): moderate versus low 3.5 (2.4, 5.1) and high versus low 9.9 (5.3, 17.6). Similar results were obtained for studies of symptomatic patients. Ratios comparing the risk of no CAD among symptomatic patients were as follows: moderate versus low 0.5 (0.3, 0.8) and high versus low 0.12 (0.05, 0.2).
Conclusion
Increasing EBCT scores indicate higher risk for CAD in both asymptomatic and symptomatic patients. In general, asymptomatic patients with EBCT scores in the high category can perhaps be considered for preventive medical therapy and risk factor modification. Symptomatic patients with EBCT scores in the low category can perhaps, at least temporarily, avoid invasive coronary angiography. However, the non-uniform quality of studies and the lack of availability of individual-level data preclude the extension of our results to individual patients.
doi:10.1186/1741-7015-5-35
PMCID: PMC2228285  PMID: 18036252
21.  Drug–drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding 
Background
Anticoagulants and antiplatelet drugs (e.g., warfarin, clopidogrel and acetylsalicylic acid) are key therapeutic agents in the treatment of cardiovascular diseases. However, drug–drug interactions may lead to a greatly increased risk of gastrointestinal bleeding when these drugs are combined. We assessed whether antithrombotic drug combinations increased the risk of such bleeding in a general practice population.
Methods
We conducted a population-based, retrospective case–control study using records in the United Kingdom General Practice Research Database from 2000 through 2005. Cases were identified as patients over 18 years of age with a first-ever diagnosis of gastrointestinal bleeding. They were matched with controls by physician practice, patient age and index date (date of diagnosis of bleeding). All eligible patients had to have at least 3 years of follow-up data in the database. Drug exposure was considered to be any prescription issued in the 90 days before the index date.
Results
There were 4028 cases with a diagnosis of gastrointestinal bleeding and 40 171 matched controls. The prescribing of acetylsalicylic acid with either clopidogrel (adjusted rate ratio [RR] 3.90, 95% confidence interval [CI] 2.78–5.47) or warfarin (adjusted RR 6.48, 95% CI 4.25–9.87) was associated with a greater risk of gastrointestinal bleeding than that observed with each drug alone. The same was true when a nonsteroidal anti-inflammatory drug was combined with either clopidogrel (adjusted RR 2.93, 95% CI 1.74–4.93) or warfarin (RR 4.60, 95% CI 2.77–7.64).
Interpretation
Drug combinations involving antiplatelets and anticoagulants are associated with a high risk of gastrointestinal bleeding beyond that associated with each drug used alone. Physicians should be aware of these risks to better assess their patients' therapeutic risk–benefit profiles.
doi:10.1503/cmaj.070186
PMCID: PMC1942107  PMID: 17698822
22.  Treating the right patient at the right time: Access to specialist consultation and noninvasive testing 
The Canadian Journal of Cardiology  2006;22(10):819-824.
The Council of the Canadian Cardiovascular Society commissioned working groups to examine issues of access to, and wait times for, various aspects of cardiovascular care. The present article summarizes the deliberations on targets for medically acceptable wait times for access to cardiovascular specialist evaluation and on the performance of non-invasive testing needed to complete this evaluation. Three categories of referral indications were identified: those requiring hospitalization due to substantial ongoing risk of mortality and morbidity; those requiring an expedited early review in an ambulatory setting; and, finally, a larger category in which delays of two to six weeks can be justified. The proposed wait time targets will provide guidance on the timeliness of care to busy clinicians charged with the care of patients with cardiovascular disease, help policy makers appreciate the clinical challenges in providing access to high quality care, and highlight the critical need for a thoughtful review of cardiology human resource requirements. Wait time implementation suggestions are also included, such as the innovative use of disease management and special need clinics. The times proposed assume that available clinical practice guidelines are followed for clinical coronary syndrome management and for treatment of associated conditions such as hypertension, diabetes, renal disease, smoking cessation and lipid disorders. Although media attention tends to focus on wait times for higher profile surgical procedures and high technology imaging, it is likely that patients face the greatest wait-related risk at the earlier phases of care, before the disease has been adequately characterized.
PMCID: PMC2569014  PMID: 16957798
Access; Canadian Cardiovascular Society; Consultation; Noninvasive testing; Wait times
23.  Drotrecogin alfa (activated) in severe sepsis: a systematic review and new cost-effectiveness analysis 
BMC Anesthesiology  2007;7:5.
Background
Activated drotrecogin alfa (human activated protein C, rhAPC), is produced by recombinant DNA technology, and purports to improve clinical outcomes by counteracting the inflammatory and thrombotic consequences of severe sepsis. Controversy exists around the clinical benefits of this drug and an updated economic study that considers this variability is needed.
Methods
A systematic literature review was performed using Medline, Embase and the International Network of Agencies for Health Technology Assessment (INAHTA) databases to determine efficacy, safety and previous economic studies. Our economic model was populated with systematic estimates of these parameters and with population life tables for longer term survival information. Monte Carlo simulations were used to estimate the incremental cost-effectiveness ratios (ICERs) and variance for the decision analytic models.
Results
Two randomized clinical trials (RCTS) of drotrecogin alfa in adults with severe sepsis and 8 previous economic studies were identified. Although associated with statistical heterogeneity, a pooled analysis of the RCTs did not show a statistically significant 28-day mortality benefit for drotrecogin alfa compared to placebo either for all patients (RR: 0.93, 95% CI: 0.69, 1.26) or those at highest risk as measured by APACHE II ≥ 25 (RR: 0.90, 95% CI: 0.54, 1.49). Our economic analysis based on the totality of the available clinical evidence suggests that the cost-effectiveness of drotrecogin alfa is uncertain (< 59% probability that incremental cost-effectiveness ratio (ICER) life year gained (LYG) ≤ $50,000/LYG) when applied to all patients with severe sepsis. The economic attractiveness of this therapy improves when administered to those at highest risk as assessed by APACHE II ≥ 25 (93% probability ICER ≤ $50,000/LYG) but these results are not robust to different measures of disease severity.
Conclusion
The evidence supporting the clinical and economic attractiveness of drotrecogin alfa is not conclusive and further research appears to be indicated.
doi:10.1186/1471-2253-7-5
PMCID: PMC1929064  PMID: 17592639
24.  Drug-eluting stents 
doi:10.1503/cmaj.1070033
PMCID: PMC1867847
25.  Pravastatin and cancer: an unproven association 
doi:10.1503/cmaj.061487
PMCID: PMC1800313  PMID: 17325331

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