Statin adherence and the risk of major coronary events in patients with diabetes: a nested case-control study

AIMS

To evaluate whether good statin adherence is associated with a reduced incidence of major coronary events (MCEs) among diabetic patients with and without coronary heart disease (CHD).

METHODS

Using data derived by linkage of nationwide health databases in Finland, we conducted a nested case–control analysis of 3513 cases with an MCE, a composite of acute myocardial infarction and/or coronary revascularization, and 20 090 matched controls identified from a cohort of 60 677 statin initiators with diabetes. Cases and controls were matched according to gender, time of cohort entry and duration of follow-up and further classified to two risk groups according to the presence of CHD at statin initiation. The incidence of MCEs was compared between patients with good statin adherence (the proportion of days covered ≥80%) and patients with poor statin adherence (<80%). Odds ratios (OR) for MCEs were estimated by conditional logistic regression adjusting for several covariables.

RESULTS

Good statin adherence was associated with a reduced incidence of MCEs in those with prior CHD [OR 0.84 (95% CI 0.74–0.95)] and in those without it [OR 0.86 (95% CI 0.78–0.95)]. The association persisted among those followed up for 5 years or longer [OR 0.77 (95% CI 0.58–1.02) and OR 0.79 (95% CI 0.66–0.94) respectively]. In sensitivity analyses, a reduced MCE incidence was observed also in those without any documented cardiovascular disease (CVD) at statin initiation [OR 0.87 (95% CI 0.78–0.96) overall and OR 0.80 (95% CI 0.66–0.97) for those followed up 5 years or longer].

CONCLUSIONS

In patients with diabetes, good adherence to statins predicts reduced incidence of MCEs irrespective of the presence of CHD at statin initiation.     

Exploring epistatic relationships of NO biosynthesis pathway genes in susceptibility to CHD

Aim:

To assess the epistatic relationships of nitric oxide (NO) biosynthesis pathway genes in susceptibility to coronary heart disease (CHD).

Methods:

A total of 2142 subjects enrolled in two case-control studies was genotyped for 7 single-nucleotide polymorphisms (SNP) within NO biosynthesis pathway genes using TaqMan assays. The association analyses were performed at both SNP and haplotype levels. Two-way SNP-SNP interactions and high-order interactions were tested using multiple unconditional logistic regression analyses and generalized multifactor dimensionality reduction (GMDR) analyses, respectively.

Results:

Two alleles (rs1049255*C and rs841*A) were identified that were significantly associated with increased risk of CHD after adjusting for all confounders (OR=1.21, 95% CI: 1.06−1.39, combined P=0.001, P_corr=0.007 and OR=1.30, 95% CI 1.12−1.50, combined P<0.001, P_corr<0.001, respectively). Significant two-way SNP–SNP interactions were found between SNP rs2297518 and these two significant polymorphisms, affecting the risk of CHD (P<0.001 for both). No significant high-order interactions were identified.

Conclusion:

The results suggested that two-way SNP–SNP interactions of polymorphisms within NO biosynthesis pathway genes contribute to CHD risk.     

Correlation of paired toxic plasma and saliva paracetamol concentrations following deliberate self-poisoning with paracetamol

AIMS

Paracetamol is commonly used in deliberate self poisoning (DSP) and requires blood sampling to refine risk assessment. We aimed to test the agreement between plasma and saliva paracetamol concentrations in the toxic range in DSP.

METHODS

Contemporaneous paired plasma and saliva paracetamol concentrations were measured. Saliva was collected using a Sarstedt Salivette® device and the concentration was measured using a colorimetric method.

RESULTS

Fifty-six patients (44, 78% female) median age 26 years (IQR 20–41) were enrolled. The median reported paracetamol ingestion was 10 g (IQR 6–14). Specimens were collected at a median of 4 h (IQR 4–5.3) post ingestion. The median plasma and saliva paracetamol concentrations were 29 mg l⁻¹ (IQR 8–110) and 38 mg l⁻¹ (IQR 10–105) respectively [mean difference 8 mg l⁻¹, 95% confidence interval (CI) 2, 14]. Lin''s concordance correlation was 0.97 (95% CI 0.96, 0.98). There were 15 patients who were treated with N-acetylcysteine. Their median reported paracetamol ingestion was 14 g (IQR 10–23) and samples were collected at a median of 4 h post ingestion. The median plasma and saliva paracetamol concentrations were 167 mg l⁻¹ (IQR 110–200) and 170 mg l⁻¹ (IQR 103–210) respectively (mean difference 15 mg l⁻¹, 95% CI −4, 35). Lin''s concordance correlation was 0.94 (95% CI 0.88, 0.99). No patient needing treatment would have been missed using saliva concentrations only.

CONCLUSIONS

The agreement between the indications for treatment of paracetamol DSP based on plasma and saliva paracetamol concentrations extends into the toxic range, but with slightly lower agreement. Saliva may hold promise as a non-invasive method to risk stratify paracetamol poisoning.     

Use and discontinuation of hormone replacement therapy in women with myocardial infarction: a nationwide study

AIM

To characterize the pattern of use and discontinuation of postmenopausal hormone replacement therapy (HRT) in women with myocardial infarction (MI) before and after 2002, where the general use of HRT dropped drastically subsequent to the results of the Women''s Health Initiative trial.

METHODS

All Danish women aged ≥40 years hospitalized with MI in the period 1997 to 2005 and their use of HRT were identified by individual-level-linkage of nationwide registers of hospitalization and drug dispensing from pharmacies. Characteristics associated with HRT use at time of MI and subsequent HRT discontinuation were analysed by multivariable logistic regression.

RESULTS

In the study period, 34 778 women were discharged after MI. Of these, 3979 (11.4%) received HRT at the time of MI and their most used categories of HRT were vaginal oestrogen and oral oestrogen alone (46.6% and 28.7%, respectively). The percentage of women who continued HRT during the first year after discharge was 85.0% in the period 2000–2002 and had decreased to 79.6% in the period 2003–2005. Vaginal oestrogen use was associated with overall discontinuation of HRT (odds ratio [OR] 1.37, 95% confidence interval [CI] 1.10, 1.72), whereas use of oral oestrogen alone and use of oral cyclic combined oestrogen/progestogen were associated with change of HRT after MI (OR 2.33, 95% CI 1.10, 4.93 and OR 2.94, 95% CI 1.35, 6.39, respectively).

CONCLUSION

The majority of women experiencing an MI during ongoing HRT continued HRT after discharge and this pattern of HRT use did not change markedly after 2002.     

Use of beta2 agonists and risk of acute myocardial infarction in patients with hypertension

AIM

Observational retrospective studies of the association between use of β₂ agonists and the risk of acute myocardial infarction (MI) have demonstrated conflicting results, particularly among first-time users. The aim of this study was to examine the association between β₂ agonist use and first nonfatal acute MI.

METHODS

We conducted a case–control study (2476 cases) nested in a cohort of antihypertensive drug users in the Dutch PHARMO RLS database. PHARMO RLS consists of drug dispensing linked to the national hospitalizations register. Each case of nonfatal acute MI was matched with up to 12 control patients by gender, age and region. Drug and disease history and the severity of the underlying respiratory disease were adjusted for.

RESULTS

Risk of acute MI was increased in current β₂ agonist users [crude odds ratio (OR) 1.36, 95% confidence interval (CI) 1.15, 1.61]. However, this excess risk was reduced after adjustment for severity of asthma and chronic obstructive pulmonary disease (adjusted OR 1.18, 95% CI 0.93, 1.49). The risk was highest in patients with ischaemic heart disease and low cumulative dose of β₂ agonists (adjusted OR 2.47, 95% CI 1.60, 3.82).

CONCLUSION

Most users of β₂ agonists did not have an increased risk of acute MI. Only patients with ischaemic heart disease with low cumulative exposure to β₂ agonists had an increased risk of acute MI. It is likely that this increased risk was related to latent cardiovascular disease rather than to the direct effects of β₂ agonists.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Use of β₂ agonists has been associated with tachycardia, an abnormal ECG and atrial fibrillation.
• Previous observational studies of the association between use of β₂ agonists and the risk of acute myocardial infarction (MI) have demonstrated conflicting results.
• Instead of a causal effect, the positive association between β₂ agonist use and MI may be explained by latent ischaemic heart disease, which has symptoms that appear similar to respiratory complaints in chronic obstructive pulmonary disease.

WHAT THIS STUDY ADDS

• The majority of β₂ agonist users in our study population did not have an increased risk of nonfatal acute MI.
• Only patients with ischaemic heart disease and who had recently started β₂ agonists had an increased risk of acute MI.
• It is likely that this increased risk was related to latent cardiovascular disease rather than direct effects of β₂ agonists.

     

Risk of digoxin intoxication in heart failure patients exposed to digoxin�Cdiuretic interactions: a population-based study

AIMS

To quantify the digoxin intoxication risk associated with exposure to digoxin–diuretic interactions, and evaluate whether the risk varies by diuretic type, individually or in combination.

METHODS

This was a population-based nested case–control study in which data from the National Health Insurance Research Database (NHIRD) in Taiwan were analysed.

RESULTS

The study cohort comprised 154 058 heart failure (HF) patients taking digoxin between 2001 and 2004, in whom digoxin intoxication requiring a hospitalization (ICD-9 code 972.1) occurred in 595 cases. A total of 28 243 matched controls were also selected for analysis. Cases were 3.08 times (adjusted OR 3.08, 95% CI 2.50, 3.79) more likely to have been prescribed diuretic medication in the previous month than controls. Regarding the class of diuretics, loop diuretics carried the greatest risk (adjusted OR 2.97, 95% CI 2.35, 3.75), followed by thiazides (OR 2.36, 95% CI 1.70, 3.29) and potassium-sparing diuretics (OR 1.72, 95% CI 0.83, 3.56). The risk was also observed to vary with different combinations of diuretics, and the loops/thiazides/potassium-sparing diuretics combination carried the greatest risk (adjusted OR 6.85, 95% CI 4.93, 9.53). Among the individual diuretics examined, hydrochlorothiazide carried the greatest risk (adjusted OR 4.63, 95% CI 2.50, 8.57).

CONCLUSIONS

This study provided empirical evidence that digoxin–diuretic interactions increased the risk of hospitalization for digoxin intoxication in HF patients. The risk was particularly high for concomitant use of digoxin with a combination of loop diuretics, thiazide and potassium-sparing diuretics. The combined use of digoxin and diuretics should be avoided if possible.     

The risk of coronary thrombosis with cyclo-oxygenase-2 inhibitors does not vary with polymorphisms in two regions of the cyclo-oxygenase-2 gene

AIMS

To investigate whether polymorphisms of the cyclo-oxygenase-2 (COX-2) gene modify the adverse cardiovascular effects of COX-2 inhibitors.

METHODS

A case control study was conducted in the Hunter Region of New South Wales, Australia. Cases (n = 460) were hospitalized with acute coronary syndrome (ACS). Controls (n = 640) were recruited from the electoral rolls. Structured interviews gathered information on variables including recent ingestion of non-steroidal anti-inflammatory drugs (NSAIDs). Targeted genotyping of rs 20417(G > C) and rs5275 (T > C) polymorphisms was performed by real-time polymerase chain reaction using allele-specific probes

RESULTS

Ingestion of any NSAID in the week prior to interview was associated with an elevated risk for ACS: adjusted odds ratio 1.8 (1.2, 2.5). The rs 20417 and rs 5275 polymorphisms were not singly associated with risk for ACS: adjusted odds ratios 1.1 (0.80, 1.5) and 1.2 (0.88, 1.5), respectively. Individually, the polymorphisms did not modify the risk of ACS with the drugs. When analyses were conducted by haplotype, the adjusted odds ratio with celecoxib or rofecoxib in individuals who had one or two copies of the ‘low risk’ haplotype (no GT) was 1.2 (0.29, 5.0), compared with 2.1 (1.1, 4.0) with the ‘high risk’ haplotype (one or two copies of GT).

CONCLUSIONS

We found little evidence of a gene/drug interaction. We found a statistically non-significant trend toward a lower risk of coronary events with NSAIDs in the presence of the ‘low risk’ haplotype. Even if confirmed, the clinical utility of the finding would be limited as this haplotype is carried by a minority of the population.     

Impact of allopurinol use on urate concentration and cardiovascular outcome

AIMS

To characterize patients with urate measurements by urate-lowering therapy (ULT) use and to study the impact of allopurinol treatment on cardiovascular and mortality outcomes.

METHODS

A cohort study using a record-linkage database. The study included 7135 patients aged ≥60 years with urate measurements between 2000 and 2002 followed up until 2007. A Cox regression model was used. The association between urate levels, dispensed allopurinol and cardiovascular hospitalization and mortality was determined.

RESULTS

Six thousand and forty-two patients were not taking ULT and 45.9% of those (2774 of 6042) had urate concentrations ≤6 mg dl⁻¹. Among 1035 allopurinol users, 44.7% (45.6% for men and 43.3% for women) reached target urate concentration. There was no significant increased risk of cardiovascular events for allopurinol users when compared with non-ULT users [adjusted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.95–1.26] and the non-ULT group with urate >6 mg dl⁻¹ (adjusted HR 1.07, 95% CI 0.89–1.28). Within the allopurinol use cohort, cardiovascular event rates were 74.0 (95% CI 61.9–86.1) per 1000 person years for the 100 mg group, 69.7 (49.6–89.8) for the 200 mg group and 47.6 (38.4–56.9) for the ≥300 mg group. Compared with low-dose (100 mg) users, high-dose (≥300 mg) users had significant reductions in the risk of cardiovascular events (adjusted HR 0.69, 95% CI 0.50–0.94) and mortality (adjusted HR 0.75, 95% CI 0.59–0.94).

CONCLUSIONS

Less than 50% of patients taking allopurinol reached target urate concentration. Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality.     

Polymorphisms of genes in nitric oxide-forming pathway associated with ischemic stroke in Chinese Han population

Aim:

To investigate the association of polymorphisms in four critical genes implicated in the NO-forming pathway with ischemic stroke (IS) in a Chinese Han population.

Methods:

DNA samples of 558 IS patients and 557 healthy controls from Chinese Han population were genotyped using the Taqman^TM 7900HT Sequence Detection System. Six SNPs (rs841, rs1049255, rs2297518, rs1799983, rs2020744, rs4673) of the 4 related genes (eNOS, iNOS, GCH1, and CYBA) in the NO forming pathway were analyzed using the SPSS 13.0 software package for Windows.

Results:

One SNP located in the intron of GCH1 (rs841) was associated with IS independent of the traditional cardiovascular risk factors in co-dominant and dominant models (P=0.003, q=0.027; P=0.00006, q=0.0108; respectively). Moreover, the combination of rs1049255 CC+CT and rs841 GA+AA genotypes was associated with significantly higher risk for IS after adjustments (OR=1.73, 95% CI: 1.27–2.35, P<0.0001, q<0.0001).

Conclusion:

The data suggest that genetic variants within the NO-forming pathway alter susceptibility to IS in Chinese Han population. Replication of the present results in other independent cohorts is warranted.     

Meta-analysis on the association between non-steroidal anti-inflammatory drug use and ovarian cancer

AIM

Animal and in vitro studies suggest that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may be associated with reduced risk for ovarian cancer. However, results from these studies have been inconsistent. The aim of our study was to review and summarize the evidence provided by longitudinal studies on the association between NSAID use and ovarian cancer risk.

METHODS

A comprehensive literature search for articles published up to December 2011 was performed. Prior to performing a meta-analysis, the studies were evaluated for publication bias and heterogeneity. Relative risk (RR) or odds ratios (OR) were calculated.

RESULTS

Seventeen reports (13 case–control studies, one clinical trial and three cohort studies), published between 1998 and 2011 were identified. There was no evidence of an association between aspirin use and ovarian cancer risk based on a random-effects model (RR = 0.91, 95% confidence interval (CI) 0.82, 1.01) or a fixed-effects model (RR = 0.94, 95% CI 0.87, 1.01). Similarly, we did not find strong evidence of an association between non-aspirin NSAID use and ovarian cancer using a random-effects model (RR = 0.89, 95% CI 0.74, 1.08) or a fixed-effects model (RR = 0.86, 95% CI 0.76, 0.98). Furthermore, our analysis did not show a strong association between frequency or duration of non-aspirin-NSAID use and ovarian cancer.

CONCLUSIONS

Our findings indicate that there is no strong evidence of an association between aspirin/NA-NSAID use and ovarian cancer. However, this subject deserves further investigation.     

Antidepressant use and risk of coronary heart disease: meta-analysis of observational studies

Aims

Our goal was to evaluate the association between antidepressant use and the risk of coronary heart disease (CHD) among subjects with no history of coronary heart disease.

Methods

A search of Medline, EMBASE, PsycINFO and the Cochrane Library was performed in January 2013. Two authors independently reviewed and selected eligible observational studies, based on predetermined selection criteria. Pooled relative risks (RRs) with confidence intervals (CIs) were calculated using random-effects or fixed-effects models.

Results

Sixteen observational studies (seven case–control studies and nine cohort studies) were included in the final analysis. There was no association between selective serotonin reuptake inhibitor use and the risk of CHD overall [odds ratio (OR), 0.93; 95% CI, 0.65–1.33] or in subgroup meta-analysis of case–control studies (OR, 0.91; 95% CI, 0.60–1.37) and cohort studies (RR, 0.96; 95% CI, 0.59–1.55). The use of tricyclic antidepressant was associated with an increased risk of CHD overall (OR, 1.51; 95% CI, 1.07–2.12), but it was observed only in case–control studies (OR, 1.56; 95% CI, 1.24–1.96) and low-quality studies (OR, 1.49; 95% CI, 1.20–1.85) in the subgroup meta-analyses.

Conclusions

This meta-analysis of observational studies in subjects with no history of CHD suggests that neither selective serotonin reuptake inhibitor nor tricyclic antidepressant use is associated with an increased risk of CHD.