Statins for primary prevention of cardiovascular disease and the risk of acute kidney injury.

PURPOSE: To investigate the risk of acute kidney injury (AKI) in subjects initiating statin therapy for primary prevention of cardiovascular disease (CVD). METHODS: A nationwide cohort study using French hospital discharge and claims databases was performed, studying subjects from the general population aged 40 to 75 years in 2009, with no history of CVD and no lipid-lowering drugs during the preceding 3-year period, followed for up to 7 years. Exposure to statins (type, dose, and time since first use) and to other drugs for CVD risk was assessed. The primary outcome was hospital admission for AKI. RESULTS: The cohort included 8 236 279 subjects, 818 432 of whom initiated a statin for primary prevention. During 598 487 785 person-months exposed to statins, 700 events were observed, corresponding to an incidence of AKI of 4.59 per 10 000 person-years (7.01 in men, 3.01 in women). AKI mainly occurred in the context of organ failure, sepsis, and genitourinary disease. A 19% increased rate of AKI (hazard ratio = 1.19, 95%CI: 1.08-1.31) was observed in men exposed to statins, whereas no increase in the overall risk of AKI was observed in women. However, exposure to high-potency statins was associated with a 72% to 116% increased risk in both genders and a dose-effect relationship observed for rosuvastatin and atorvastatin. No temporal pattern of occurrence nor interaction with drugs for CVD risk was observed. CONCLUSIONS: Although the overall risk of AKI appears moderately increased, more attention should be paid to renal function in subjects taking statins for primary prevention both in clinical practice and from a research viewpoint.

Statins for primary prevention and rhabdomyolysis: A nationwide cohort study in France.

AIMS: The purpose of this study was to investigate the risk of rhabdomyolysis in subjects initiating statin therapy for primary prevention of cardiovascular disease, focusing on the type of statin, dose and time since initiation. METHODS AND RESULTS: A nationwide cohort study using French hospital discharge and claims databases was performed, studying subjects from the general population 40-75 years in 2009, with no history of cardiovascular disease and no lipid-lowering drugs during the preceding three-year period, followed for up to seven years. The primary outcome was hospitalization for rhabdomyolysis. Event-free survival analysis and case-time-control analysis were both performed, separately by gender. The cohort included 8,236,667 subjects, 969,460 of whom initiated a lipid-lowering drug for cardiovascular disease primary prevention. During 18,407,391 person-months exposed to statins, 168 events were observed, corresponding to an incidence of rhabdomyolysis of 1.10 per 10,000 person-years (1.54 in men vs 0.81 in women); 10/168 cases were fatal, and 18/168 and 57/168 cases occurred during the first month and first trimester of treatment, respectively. Survival analysis did not reveal any increased overall risk (hazard ratio = 1.02 (0.83-1.25) in men and 0.76 (0.60-0.96) in women). However, exposure to high-potency statins was associated with an increased risk in men (hazard ratio = 1.93 (1.27-2.94)). Rosuvastatin 20 mg (in men and women) and simvastatin 40 mg (in men) were associated with hazard ratios > 5. Case-time-control analyses showed similar patterns of risk. Drug interactions did not appear to significantly contribute to rhabdomyolysis events in this study. CONCLUSION: Although the overall risk of statin-associated rhabdomyolysis in the context of primary prevention was not increased, the first months of treatment and the use of high-potency statins represent at-risk situations, which require appropriate monitoring, especially in men.

Is There a Cardiotoxicity Associated With Metallic Head Hip Prostheses? A Cohort Study in the French National Health Insurance Databases.

BACKGROUND: There are four distinguishable types of THA devices in wide use, as defined by the femoral and acetabular bearing surfaces: metal-on-polyethylene (MoP), ceramic-on-polyethylene (CoP), metal-on-metal (MoM), and ceramic-on-ceramic (CoC). Metallic head THAs (MoP and MoM) can potentially induce cardiac toxicity because cobalt species, generated at the head-neck trunnion, and in the case of MoM devices, at the articular surface as well, can be absorbed systemically. However, studies have provided inconsistent results. QUESTIONS/PURPOSES: The purpose of this study was to assess the risk of dilated cardiomyopathy (DCM) or heart failure (HF) associated with metallic head THAs using data from the French national health insurance databases. METHODS: Between 2008 and 2011 in France, 399,968 patients ≥ 55 years had a first THA. A total of 127,481 were excluded after we applied the exclusion criteria regarding arthroplasty and 17,137 as a result of a history of DCM/HF, recorded in the French national health insurance reimbursement databases, between January 1, 2006, and the date of inclusion. The final cohort included 255,350 individuals (43% men; mean age 72 ± 9 years). Of them, 93,581 (37%) had been implanted with MoP, 58,095 (23%) with CoP, 11,298 (4%) with MoM, and 92,376 (36%) with CoC THAs. Patients were followed until December 2015. Patients with incident DCM/HF were identified by a new entitlement to the long-term disease scheme or a first hospitalization with a diagnosis of DCM or HF. MoP and CoP THAs are generally implanted in old patients, whereas MoM and CoC are mostly indicated in young, active male patients. Thus, to consider the specific indications of the bearing couples, analyses were separately performed in two distinct subcohorts, one comprising patients with MoP or CoP and one comprising patients with MoM or CoC THA. In each subcohort, the DCM/HF risk was compared between patients with metallic head versus nonmetallic head THAs (MoP versus CoP, MoM versus CoC). Hazard ratios (adjusted HRs) of incident DCM/HF were estimated using Cox models adjusted for baseline sex, age, THA characteristics (fixation technique with cement, use of a modular femoral neck), and comorbidities at baseline. Cox models were stratified by sex and age. RESULTS: The crude incidence of DCM/HF per 100 person-years was 2.4 in patients with MoP, 1.8 with CoP, 1.2 with MoM, and 1.1 with CoC THAs. Overall, metallic head THAs were associated with a slight increase in DCM/HF risk (MoP versus CoP: adjusted HR, 1.08; 95% confidence interval [CI], 1.05-1.12; p < 0.001; MoM versus CoC: adjusted HR, 1.11; 95% CI, 1.03-1.19; p = 0.007). In the MoM-CoC subcohort, the risk tended to be more pronounced with MoM versus CoC THAs in women (MoM versus CoC: adjusted HR, 1.20; 95% CI, 1.07-1.35; p = 0.002) and patients aged ≥ 75 years (MoM versus CoC: adjusted HR, 1.16; 95% CI, 1.04-1.29; p = 0.009). CONCLUSIONS: Metallic head THAs were associated with a slightly increased DCM/HF risk, especially with MoM in women and older patients. Some caveats should be mentioned: severity of DCM or HF was not available and residual confounding cannot be ruled out despite considering many covariates. Our findings suggest that cardiac function should be regularly monitored in patients with metallic head THAs. Further investigations should be planned on large international cohorts. LEVEL OF EVIDENCE: Level III, therapeutic study.

Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease.

IMPORTANCE: An increased risk of lymphoma has been reported among patients receiving thiopurines for inflammatory bowel disease (IBD). The risk of lymphoma associated with anti-tumor necrosis factor (TNF) agents either alone or in combination with thiopurines is uncertain. OBJECTIVE: To assess the risk of lymphoma associated with thiopurines and anti-TNF agents, used alone or in combination, for the management of IBD. DESIGN, SETTING, AND PARTICIPANTS: Nationwide cohort study based on French National Health Insurance databases. Patients aged 18 years or older identified with IBD were included from January 1, 2009, through December 31, 2013, and followed up until December 31, 2015. EXPOSURES: At each time of the follow-up, patients were categorized as being exposed to thiopurine monotherapy, anti-TNF monotherapy, or combination therapy, or being unexposed. MAIN OUTCOMES AND MEASURES: The primary outcome was incident lymphoma. RESULTS: Among the 189 289 patients included (54% women; median age, 43 years [interquartile range, 32-56 years]) and followed up for a median of 6.7 years, 123 069 were never exposed during follow-up, 50 405 were exposed to thiopurine monotherapy, 30 294 to anti-TNF monotherapy, and 14 229 to combination therapy. Overall, 336 lymphoma cases occurred: 220 in unexposed patients (incidence rate [IR] per 1000 person-years, 0.26; 95% CI, 0.23-0.29), 70 in patients exposed to thiopurine monotherapy (IR, 0.54; 95% CI, 0.41-0.67), 32 in patients exposed to anti-TNF monotherapy (IR, 0.41; 95% CI, 0.27-0.55), and 14 in patients exposed to combination therapy (IR, 0.95; 95% CI, 0.45-1.45). In a multivariable Cox model, compared with unexposed patients, the risk of lymphoma was higher among those exposed to thiopurine monotherapy (adjusted hazard ratio [aHR], 2.60; 95% CI, 1.96-3.44; P < .001), anti-TNF monotherapy (aHR, 2.41; 95% CI, 1.60-3.64; P < .001), or combination therapy (aHR, 6.11; 95% CI, 3.46-10.8; P < .001). The risk was higher in patients exposed to combination therapy vs those exposed to thiopurine monotherapy (aHR, 2.35; 95% CI, 1.31-4.22; P < .001) or anti-TNF monotherapy (aHR, 2.53; 95% CI, 1.35-4.77; P < .001). CONCLUSIONS AND RELEVANCE: Among adults with IBD, the use of thiopurine monotherapy or anti-TNF monotherapy was associated with a small but statistically significant increased risk of lymphoma compared with exposure to neither medication, and this risk was higher with combination therapy than with each of these treatments used alone. These findings may inform decisions regarding the benefits and risks of treatment.

Pulse pressure monitoring of open antihypertensive therapy.

BACKGROUND: Pulse pressure (PP) >60 mm Hg is an independent predictor of cardiovascular (CV) risk. Controlled studies showed that, unlike systolic and diastolic blood pressure (BP), PP responds minimally to placebo or no treatment. METHODS: The aim of this study was to evaluate PP as a parameter of BP control in general practice. This open multicenter study involved 1841 primary care physicians with postinclusion visits at months 3, 6, and 9. Six thousand one hundred ten hypertensive patients participated in this study. They had a baseline PP >60 mm Hg and were divided into five antihypertensive therapy categories: 1) no antihypertensive therapy; 2) antihypertensive therapy incorporating neither an angiotensin-converting enzyme inhibitor (ACEI) nor a diuretic; 3) ACEI but no diuretic; 4) diuretic but no ACEI; and 5) ACEI + diuretic. In each category, any other antihypertensive agent could be added to lower the PP below 60 mm Hg. The PP was calculated from systolic and diastolic BP using a semiautomatic oscillometric sphygmomanometer; new CV events were assessed. RESULTS: At 9 months, 95% of patients were receiving the ACEI + diuretic combination versus <10% at inclusion. During this period PP decreased below 60 mm Hg in 48% of the patients, and persisted above 80 mm Hg in less than 5%. New CV events occurred in 221 patients and were predicted by a positive CV history and age <50 years (odds ratio [OR]: 2.49; 95% confidence interval [CI]: 1.46-4.55). In patients without a CV history, the only predictor of decreased CV events was ACEI + diuretic combination (OR: 0.50; 95% CI: 0.30-0.90). In the overall population, age <50 years and PP <60 mm Hg predicted a lack of new CV events (OR: 0.55; 95% CI: 0.32-0.88). CONCLUSIONS: The PP is an appropriate tool for evaluating open chronic antihypertensive therapy, and help to predict, under an ACEI + diuretic combination, the occurrence of new CV events.

Gene polymorphisms of the renin-angiotensin system and age-related changes in systolic and diastolic blood pressure in subjects with hypertension.

BACKGROUND: Few studies have examined to what extent genes might modulate the changes of systolic and diastolic blood pressure (BP) with age although, in older populations, systolic BP and diastolic BP vary with age in opposite directions. METHODS: This study involved 205 men and 99 women with either systolic-diastolic or isolated systolic hypertension. Age was > 50 years. Using polymerase chain reaction, four gene polymorphisms related to the renin-angiotensin system were independently investigated in men and women. Adjustments to cardiovascular and renal risk factors as well to the sodium/potassium extracellular space ratio were performed. RESULTS: Regarding the angiotensin-converting enzyme (ACE) gene polymorphism, in men > 50 years of age, the slope (mm Hg per unit of age) of the age-diastolic BP (and not age-systolic BP) relationships significantly (P = .0092) differed between genotypes: - 0.79 +/- 0.15 (P < .0001) for the DD genotype, -0.53 +/- 0.10 for the ID genotype (P < .0001), and -0.23 +/- 0.11 for II genotypes (P = NS). Such findings were not observed in the female population in which the age-diastolic BP curves were substantially flatter than in men. No comparable results were observed for gene polymorphisms related either to angiotensinogen or to angiotensin II type 1 receptor. CONCLUSIONS: In men > 50 years of age, the ACE gene polymorphism modulates the physiologic age-induced reduction of diastolic BP. The D allele might contribute to enhance this reduction, a finding that needs confirmation using prospective studies.

Angiotensin-converting enzyme D/I gene polymorphism and age-related changes in pulse pressure in subjects with hypertension.

UNLABELLED: Background- Few studies have examined the possible influence of gene polymorphisms on the increase of systolic blood pressure (SBP) and pulse pressure (PP) with age, although in older populations, SBP>160 mm Hg or PP>60 mm Hg are strong mechanical factors predicting cardiovascular mortality. METHODS AND RESULTS: This cross-sectional study involved 315 men and 154 women with either systolic-diastolic or isolated systolic hypertension. Using polymerase chain reaction, the angiotensin-converting enzyme (ACE) D/I gene polymorphism was investigated separately in men and women, enabling us to determine the relationships between age and PP, SBP, and diastolic blood pressure (DBP) for each genotype in each population. In men, most of which were under 50 years of age, the slope of the age-PP and age-SBP (but not age-DBP) relationships differed significantly between genotypes (P=0.0096 and 0.0175). The interslope difference was unmodified after adjustments involving all of the following factors together: plasma glucose, cholesterol, creatinine, potassium, body weight, tobacco consumption, mean blood pressure, and previous antihypertensive therapy. Adjustment of the two latter parameters alone significantly attenuated the interslope difference. Based on logistic regressions, the DD genotype was shown to independently predict a PP>60 mm Hg but not a SBP>160 mm Hg. CONCLUSIONS: In men, the ACE D/I gene polymorphism independently modulates age-related increase of PP, and potentially modulates the resulting cardiovascular risk. This finding requires the development of long-term follow-up.

Heart rate and pulse pressure amplification in hypertensive subjects.

BACKGROUND: Although mean blood pressure (MBP) remains unmodified along the arterial tree, pulse pressure (PP) increases physiologically from the central to the peripheral arteries. Amplification of PP is known to be influenced by heart rate (HR), but the impact of this alteration has never been tested in patients with hypertension. METHODS: A total of 712 hypertensive subjects, either treated or untreated, were divided into three classes of HR level. Carotid and brachial systolic blood pressure (SBP), carotid augmentation index, a marker of wave reflections, and carotid-brachial PP amplification were measured using applanation tonometry. RESULTS: Independent of age, sex, and antihypertensive drugs, subjects with HR >80 beats/min were characterized, in comparison with those with lower HR, by reduced carotid SBP, PP, and augmentation index, resulting in a significant increase in PP amplification. In men but not in women, this pattern was associated with higher values of brachial SBP and DBP and by higher incidences of elevated glycemia and atherosclerotic alterations. In the male population, PP amplifications was, independent of HR, associated with the presence of beta blocking agents (negative association) and elevated plasma glucose. CONCLUSIONS: Hypertensive men and women with high HR have significant PP amplifications, principally because of reduced central SBP and disturbed wave reflections. beta-blocking agents and plasma glucose independently alter PP amplification in men but not in women. Whether these opposite patterns influence the gender difference in cardiovascular risk should be prospectively studied.