Antihypertensive Drug-Gene Interactiosn and Cardiovascular Outcomes

Hypertension is a major public health hazard, because of its high prevalence and strong positive association with cardiovascular diseases. Suboptimal blood pressure control is the number one attributable risk for death in the Western world, despite the possibilities to treat hypertension. Higher pre-treatment blood pressure levels are associated with a greater antihypertensive drug response, but this relation is not specific to a particular antihypertensive drug or drug class nor can it be predicted from patients characteristics. Therefo

Interactions between five candidate genes and antihypertensive drug therapy on blood pressure

Despite the availability of effective antihypertensive drugs, there is a large variation in response to these drugs. This study investigates whether polymorphisms in the angi

Antidepressant-Warfarin Interaction and Associated Gastrointestinal Bleeding Risk in a Case-Control Study

Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users.Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those ≥18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]).Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd

Pharmacogenetic interactions of three candidate gene polymorphisms with ACE-inhibitors or beta-blockers and the risk of atherosclerosis

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: To our knowledge, there are no prior studies which investigate whether there is a drug–gene interaction between the three genes involved in the renin–angiotensin system and ACE-inhibitor therapy or β-blocker therapy with these subclinical measurements of atherosclerosis. Some studies have found an effect on blood pressure or stroke/myocardial infarction, although the results are not conclusive. WHAT THIS STUDY ADDS: The results do not indicate the presence of a strong drug–gene interaction between the use of ACE-inhibitors or β-blockers and the ACE insertion/deletion, AGT M235T or AGTR1573C/T polymorphism on the overall risk of atherosclerosis. AIMS: To investigate whether the angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen M235T or angiotensin II receptor type 1 573C/T polymorphism modify the risk of atherosclerosis associated with β-blocker or ACE-inhibitor therapy. METHODS: Data were used from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, which started in 1990 and included 7983 subjects of ≥ 55 years. In this study, 2216 subjects with hypertension were included. Three subclinical measurements were used for atherosclerosis, i.e. peripheral arterial disease, carotid atherosclerosis and aortic atherosclerosis. The interaction between antihypertensive drugs and genetic polymorphisms on the risk of atherosclerosis was determined with binary logistic regression analysis. RESULTS: The risk of aortic atherosclerosis associated with long-term (≥4 years) β-blocker treatment compared with no use of β-blockers was higher in subjects with the TT genotype than in subjects with the MM genotype of the AGT gene [synergy index (SI) = 3.36; 95% confidence interval (CI) 1.14, 9.97]. The risk of carotid atherosclerosis associated with long-term ACE-inhibitor treatment compared with no use of ACE-inhibitors was lower in subjects with the TT genotype than in subjects with the MM genotype of the AGT gene (SI = 0.20; 95% CI 0.04, 0.95). CONCLUSION: Overall, the risk of atherosclerosis in hypertensives taking a β-blocker or ACE-inhibitor-based regimen was not strongly modified by any of the three candidate gene polymorphisms