The use of antithrombotic agents and falls are independently associated with an increased risk of hemorrhagic injury. However, few studies have delineated the risk of fall-related hemorrhagic complications in persons who are taking antithrombotic therapy. The objective of this study was to compare the rates of fall-related hemorrhagic injury in hospital in-patients who are taking and not taking antithrombotic therapy.A 4-year retrospective chart review of consecutive patients who fell during admission to a 500-bed tertiary-care teaching hospital was conducted. Major hemorrhagic injuries including subdural hematomas and major bleeding/cuts, patients' use of antithrombotic medication  and their anticoagulation status at the time of their fall were recorded.A total of 2635 falls in 1861 patients were reviewed. Approximately 10% of falls caused major hemorrhagic injury. One fall resulted in a subdural hematoma. Persons taking warfarin were less likely to suffer a fall-related major hemorrhagic injury compared with persons not taking antithrombotic therapy . Logistic regression showed that fall-related major hemorrhagic injury was associated with female gender , use of aspirin  and use of clopidogrel , but not with the use of warfarin or heparin, or the intensity of anticoagulation.In this study, compared with persons taking no antithrombotic therapy, those taking warfarin had lower rates of fall-related hemorrhagic injuries. The absolute rate of the development of fall-related intracranial hemorrhagic injury such as subdural hematomas was low, even in persons taking warfarin. These counter-intuitive results may be due to selection bias, and suggest that physicians are very conservative in selecting patients for warfarin therapy, choosing only those who are sufficiently healthy to be at much lower than average risk of suffering fall-related hemorrhagic injuries. This phenomenon may lead to physicians overestimating the potential for fall-related major hemorrhagic injury in persons taking antithrombotic therapy, with the possible denial of warfarin therapy to many of those who would benefit. This perception may contribute to the care gap between the number of patients who would theoretically derive overall benefit from warfarin therapy and those who are actually receiving it. Howevet al  examinedet al  using deet al . Thus, set al . The objThe protocol was approved by the Ottawa Hospital Research Ethics Committee and is in compliance with the Helsinki Declaration. Since implementation of a fall prevention program in 1991, the Ottawa Hospital – Civic Campus, a 500-bed tertiary care teaching hospital, has had a formal policy of documenting the pertinent details of all patient-related falls occurring within the hospital. Using its dedicated falls database, the records of consecutive falls occurring over a 4-year period  were identified. The hospital policy requires completion of an incident report when patients fall. Information collected includes the time and circumstances of the fall, the type of injury (including head injury) that occurred and a categorization of its severity, and the need for subsequent follow-up. A member of the physician team must eventually review all fall incident reports, follow-up any significant injury from the fall and document this information in the hospital record and incident report.Hemorrhage (i.e. cuts or bruising) was classified as major if the immediate attention of a physician was required, or a clinically apparent intracranial hemorrhage subsequently occurred. All other hemorrhage was classified as minor.Since patient falls can be seen as a reflection of sub-optimal nursing care, the hospital has adopted a non-punitive approach to the completion of reports in order to focus on improving the process that led to the falls. The hospital recognizes that the value of the falls database is predicated on maximum completion of incident reports, leading to the assignment of nurse practitioners dedicated to ensuring the completion of the falls reports. Therefore, it is unlikely that falls leading to an injury would not be captured. During the study period, the hospital had no formal policy or guidelines governing the use of antithrombotic therapy in patients.For all identified falls, the hospital records of the corresponding in-patient admission were retrieved. Data extraction from these charts included pertinent patient demographic information, and the use of antithrombotic therapy  at the time of the fall. The indications for the use of the particular antithrombotic therapy were also recorded. Using computerized laboratory reports, the international normalized ratio (INR) and partial thromboplastin time (PTT) values that were closest to the time of the fall were also recorded. Patients' INR values at the time of the fall were determined as follows:1. If an INR had been done within 12 hours pre- or post-fall, this was accepted as the INR value at the time of the fall. For patients with both 12 hour pre- and post-fall INRs, these values were averaged.2. For patients not receiving warfarin, if an INR had not been done within 12 hours of the fall and the closest temporal INR was within the normal range (INR<1.2), this was accepted as the INR value occurring at the time of the fall. If the INR values were abnormal, then the pre- and post-INR values temporally closest to the time of the fall were averaged.3. For persons receiving warfarin at the time of the fall, if no 12 hour pre- and post fall INRs were available, then the pre- and post-fall INR values done temporally closest to the fall were averaged.4. For persons who did not have an INR while in hospital and were not receiving warfarin, their charts were reviewed for possible reasons to have an elevated INR . If these were not present, their INR were deemed to be normal (INR 1.0).For patients taking heparin, an identical approach was used for determining the PTT values at the time of their fall.The discharge summaries, nursing notes and medical notes of the hospital records were also reviewed for any immediate and subsequent complications due to the fall including head trauma, subdural hematoma, intracerebral hemorrhage, fractures, major and minor hemorrhage. Multiple falls by the same person were considered independent events. Data extractors were not blinded to the exposure status of patients or their outcomes.Statistical analysis was performed using SPSS software version 10 . Chi-square testing was performed to determine the relationship between individual demographic and clinical factors, and the occurrence of major hemorrhage. Step-wise forward logistic regression analysis was then performed with variables that had p-values < 0.20 on univariate analysis. Given that multiple statistical comparisons were performed, a p-value < 0.01 was considered statistically significant.For the 4-year period, there was a total of 2664 recorded falls in 1861 patients. Despite numerous attempts, the corresponding hospital records could not be located for 29 (1.1%) of the falls. Thus, pertinent data were available and extracted regarding 2635 falls. A significant percentage (29.4%) of patients fell more than once during their admission. The average age of the patients was 71.5 years , with most being male (55.2%).Table 1 see  shows thTable 2 see  shows thThere was also one fall possibly resulting in an intracerebral hemorrhage occurring in a 60 year old female. She also suffered head trauma from her fall, but was not taking any antithrombotic therapy, and her INR and PTT values were in the normal range at the time of the fall. She recovered from this injury, with no apparent sequelae.The absolute rate of major hemorrhagic injury  was lower in persons taking warfarin, compared with those taking no antithrombotic therapy at all . A comparison of major hemorrhagic injury between those with normal INR values (INR = <1.3) and those in the therapeutic range (INR 2–3) showed a strong trend towards fewer complications in the group with therapeutic INRs ; INR 2–3, 6.9% (15/218); odds ratio 0.65, 95% CI; 0.38, 1.13; p = 0.15). A similar comparison between those with normal INRs and those with INRs between 3–5, showed no statistical difference in hemorrhagic complications between the two groups ; INR 3–5, 11.4% (9/79); odds ratio 1.14, 95% CI; 0.56, 2.32; p = 0.70).Univariate analysis demonstrated a very strong relationship between gender and the occurrence of fall-related major hemorrhagic injury , with females being much more likely to suffer one of these complications compared with males (13.3% (157/1181) versus 8.7% (126/1454); p < 0.001). Univariate analysis also showed that there were trends towards an increase in the occurrence of major hemorrhagic injury with increasing age (p = 0.04), increasing INR values at time of fall (p = 0.04), and the use of clopidogrel (p = 0.05) or aspirin (p = 0.20). There was no relationship between major hemorrhagic injury with PTT values at time of the fall (p = 0.27), the use of warfarin (p = 0.42) or the use of heparin (p = 0.62). Similar analyses using major bruising/cuts alone  yielded almost identical results. This was due to the occurrence of only one subdural hematoma and one intracerebral hemorrhage.Logistic regression analysis showed that the factors important in the development of major hemorrhagic injury due to falls were female gender , the use of aspirin  and the use of clopidogrel . Of note, increasing age was not an independent risk factor and there was no interaction between warfarin and aspirin use.Repeating the analyses with exclusion of all recurrent falls in individuals (n = 1861) resulted in no significant differences in the results reported above.Of note, fractures occurred in 1.4% of falls (n = 38), with 20 of these being hip fractures.Falling is a common phenomenon in both hospitalized  and commNumerous studies -15 have The overall results of this study found that persons taking warfarin were less likely to suffer a fall-related hemorrhagic injury, compared to those taking no antithrombotic therapy. This counter-intuitive result may be due to selection bias. That is, physicians were very conservative in selecting patients for warfarin therapy, choosing only those who were robust enough to be at very low risk of suffering a fall-related hemorrhagic injury. Thus, physicians possibly overestimate the potential for major hemorrhagic injury in persons taking antithrombotic therapy, leading to the possible denial of warfarin therapy to many of those in whom warfarin would otherwise be indicated. This practice may contribute to the well-documented care gap between the number of patients who would theoretically derive overall benefit from warfarin therapy and those who are actually receiving it. ,17 HowevIn this study, only 1 SDH occurred as a result of the more than 2500 falls. Therefore, it was not possible to perform meaningful statistical analyses regarding the contributors to this complication. However, the results confirm that fall-related subdural hematomas are not common in older hospitalized persons, even if they are taking antithrombotic agents. That being said, the development of the single SDH found in this study was almost certainly related to the concomitant use of warfarin and aspirin, with an associated INR of greater than 4.0.The reason(s) for this study finding that female patients have a greater risk of developing fall-related hemorrhagic injury is unclear. Age was not a factor as the mean age of female patients (71.6 years) was similar to male patients (71.5 years). Also, the percentages of female and male patients taking warfarin, heparin, clopidogrel or aspirin in this study were very similar. Other studies ,19 have The use of aspirin or clopidogrel is generally considered to be less likely to lead to major hemorrhagic injury when compared with the use of warfarin or heparin. Therefore, it was surprising to find that there was a weak, but statistically significant association between fall-related major hemorrhagic injuries and the use of aspirin or clopidogrel, but no such relationship with the use of warfarin or heparin. Again, this result may be due to selection bias, with physicians favoring the use of aspirin or clopidogrel over warfarin or heparin in persons who are less healthy and more prone to serious hemorrhagic injury if they fall.There are a number of limitations to our study. Due to the retrospective design, it was not possible to apply standardized definitions and measures when determining the occurrence, severity and consequences of falls. Also, we examined the injuries related to hospital-based falls. Therefore, it is unclear whether our results are generalizable to other settings. However, the 10.7% rate of major fall-related hemorrhagic injury  in this study is similar to previous hospital- and community-based studies ,12 that The study also has an important strength. Not all fall-related major hemorrhagic injury  is identifiable immediately after a fall. We were able to follow-up the sequelae of falling throughout the course of the patients' hospital admission. Therefore, it is unlikely that we failed to identify any serious consequences of falling in our study population.This study provides evidence that the absolute rate of the development of fall-related subdural hematomas is low, even in persons taking warfarin. Also, the lower than expected rate of fall-related hemorrhagic injury in persons taking warfarin suggests that physicians may overestimate the potential for fall-related major hemorrhagic injury in older persons taking antithrombotic therapy, leading to an overly conservative approach to assessing the risk of anticoagulant-related bleeding. This information may help close the care gap between the number of patients who would theoretically benefit from anticoagulant therapy and the number that actually receive it. Further study is necessary to delineate the characteristics of patients who are at high risk of developing fall-related hemorrhagic injury when taking antithrombotic therapy.The author(s) declare that they have no competing interests.MM and FM proposed the study. All authors participated in the design of the study and contributed to the drafting and revision of the manuscript. AB and ML conducted the chart reviews.TABLE1Aug04revised.doc : this is Table 1 entitled, "Fall-related antithrombotic use"Click here for fileTABLE2Aug04revised.doc : this is Table 2 entitled, "Consequences of falls"Click here for file


Relatively few U.S.-based studies in chronic kidney disease have focused on Asian/Pacific Islanders. Clinical reports suggest that Asian/Pacific Islanders are more likely to be affected by IgA nephropathy (IgAN), and that the severity of disease is increased in these populations.To explore whether these observations are borne out in a multi-ethnic, tertiary care renal pathology practice, we examined clinical and pathologic data on 298 patients with primary glomerular lesions  at the University of California San Francisco Medical Center from November 1994 through May 2001. Pathologic assessment of native kidney biopsies with IgAN was conducted using Haas' classification system.Among individuals with IgAN (N = 149), 89 (60%) were male, 57 (38%) white, 53 (36%) Asian/Pacific Islander, 29 (19%) Hispanic, 4 (3%) African American and 6 (4%) were of other or unknown ethnicity. The mean age was 37 ± 14 years and median serum creatinine 1.7 mg/dL. Sixty-six patients (44%) exhibited nephrotic range proteinuria at the time of kidney biopsy. The distributions of age, gender, mean serum creatinine, and presence or absence of nephrotic proteinuria and/or hypertension at the time of kidney biopsy were not significantly different among white, Hispanic, and Asian/Pacific Islander groups. Of the 124 native kidney biopsies with IgAN, 10 (8%) cases were classified into Haas subclass I, 12 (10%) subclass II, 23 (18%) subclass III, 30 (25%) subclass IV, and 49 (40%) subclass V. The distribution of Haas subclass did not differ significantly by race/ethnicity. In comparison, among the random sample of patients with non-IgAN glomerular lesions (N = 149), 77 (52%) patients were male, 51 (34%) white, 42 (28%) Asian/Pacific Islander, 25 (17%) Hispanic, and 30 (20%) were African American.With the caveats of referral and biopsy biases, the race/ethnicity distribution of IgAN differs significantly from that of other major glomerulonephridities. However, among individuals undergoing native kidney biopsy, we see no evidence of a race/ethnicity association with severity of disease in IgAN by clinical and IgAN-specific histopathologic criteria. Further studies are needed to identify populations at higher risk for progressive disease in IgAN. IgA nephropathy (IgAN) is the most common form of glomerulonephritis (GN) worldwide . ApproxiClinical reports suggest that individuals of Asian/Pacific Islander heritage are more likely to be affected by IgAN than whites, African Americans, and persons of Hispanic descent. Reports from U.S. centers have generally compared results of white and African American IgAN patients, with little or no available information on U.S. patients of Asian/Pacific Islander heritage. Studies from Japan and China have reported that more individuals with ESRD in these countries had IgAN, implying that IgAN may have a more severe disease course in certain Asian populations ,7.To explore whether IgAN was more common and severe among Asian/Pacific Islanders in our population, we examined clinical and pathologic data on 149 patients with IgAN and a random sample of 149 patients with other primary glomerular lesions  at the University of California San Francisco (UCSF) Medical Center.The records of 183 percutaneous native and transplant kidney biopsies with a diagnosis of IgAN received between November 1994 and May 2001 at the Renal Pathology Laboratory at UCSF were reviewed. Baseline demographic and clinical data included age, gender, race or ethnicity, history of kidney transplant, date of biopsy, and serum creatinine concentration at the approximate time of biopsy. In addition, the presence or absence of heavy proteinuria  and the presence or absence of hypertension at the time of biopsy were recorded. Major ethnic groups included white, Asian/Pacific Islander, Hispanic, African American, and other/unknown. Ethnicity was determined using information from patient health insurance forms and history provided at the time of biopsy. Any case in which Henoch-Schönlein purpura, systemic lupus erythematosus or chronic liver disease were considered likely diagnoses were excluded, as were cases of IgAN superimposed on a systemic disease involving the kidney . Two examiners unaware of the clinical data independently reviewed the biopsies. Biopsies displaying fewer than six glomeruli by light microscopy or insufficient immunofluorescence staining, as defined below, were also excluded. Fifteen biopsies were additionally excluded due to incomplete recovery of microscopic slides from files. Biopsies from 149 patients, including 25 kidney transplant recipients, satisfied the criteria for inclusion and provided the basis for the IgAN analytic sample.Aside from IgAN, the most commonly diagnosed primary glomerular lesions at our institution over the same time period were focal segmental glomerulosclerosis (N = 314), membranous nephropathy (N = 197) and minimal change disease (N = 147). To establish baseline race/ethnicity prevalences for our region and referral population, we collected demographic data on a computer-generated random sample of individuals with non-IgAN glomerular disease (N = 149), stratified by kidney transplant.Pathologic assessment of the IgAN native kidney biopsies was performed based on Haas' IgA nephropathy classification system . All cas2 test for categorical variables, and analysis of variance  or Kruskal-Wallis test for continuous variables. Two-tailed P-values <0.05 were considered statistically significant. SAS version 8.2 was used for all statistical analyses .Demographic and clinical data are reported as mean ± standard deviation, medians with interquartile ranges, and proportions with 95% confidence limits. Inter-ethnicity comparisons were performed using the Cochrane-Mantel-Haenzsel χPatient clinical characteristics for the IgAN group are summarized in Table P = 0.64). Sixty-six patients (44%) exhibited heavy (≥ 3 g/d) proteinuria, and 74 (50%) had documented hypertension (systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mm Hg) at the time of kidney biopsy. The fractions of patients with heavy proteinuria and hypertension at the time of kidney biopsy were not significantly different among white, Hispanic, and Asian/Pacific Islander groups.The median serum creatinine (SCr) of the IgAN cohort was 1.7 mg/dL (interquartile range 1.1–3.4 mg/dL). The median SCr of the African American group was signficantly higher (5.0 mg/dL) than the other ethnic groups; however, these calculations were based on a small sample size (N = 4) due to the low prevalence (3%) of African Americans with in our IgAN cohort. Median serum creatinine concentrations were not significantly different among white, Hispanic, and Asian/Pacific Islander groups  fell into Haas subclasses IV or V, which are known independent predictors of progressive disease and poor renal outcomes . Only 22P = 0.006) compared to patients with IgAN. In addition, the distribution of race/ethnicity differed significantly between the two groups (P < 0.001). This association of IgAN and distribution of race/ethnicity persisted even when stratified by kidney transplant .Table In a biopsy series of 244 patients with IgAN, Haas found fewer African Americans (in a major urban setting), similar to that noted in other U.S.-based studies of IgAN -11. WhilIn our study, the fraction of biopsies in subclasses I and II (18%) was similar to that observed by Haas (23%). However, we observed a higher proportion of biopsies in subclasses IV and V (64% vs. 31%), and a lower proportion of biopsies in subclass III (19% vs. 45%) compared with Haas, possibly reflecting a temporal trend towards a higher biopsy threshold along with intergrader measurement bias.In a study reviewing the pattern of glomerulonephritis in Singapore over the past two decades, Woo and colleagues reported that IgAN was the most common primary GN occurring in Singapore  . In our In contrast, based on smaller biopsy series, a striking variation in prevalence rates of IgAN has been reported from Europe and South America. In the UK, for example, Ballardie and colleagues noted comparatively low prevalence rates of IgAN in a predominantly white population  in the early 1970's. In the subsequent 15-year period, however, these investigators reported a phenomenal rise in the observed incidence of IgAN , which the investigators felt more likely reflected a higher frequency of detection rather than true rise in disease incidence. Similar prevalence rates have also been documented from isolated white populations in Finland and southern Italy ,17. In cThese differences may be partially attributed to increased screening and disparities in the indication for kidney biopsy. In Japan and South Korea, for example, school-aged children undergo annual screening for urinary abnormalities; kidney biopsy is subsequently recommended for children with evidence of proteinuria or hematuria . More coH. parainfluenzae as a causative agent of IgAN in Japanese children and adults. Such claims are supported by studies showing the glomerular deposition of outer membrane H. parainfluenzae antigens and greater levels of plasma IgA1 antibody against OMHP in Japanese patients with IgAN  [H. parainfluenzae colonization and/or infection has yet to be established.Although the etiology of IgAN remains unknown, there exists a strong suspicion for an environmental antigen trigger combined with a genetic susceptibility factor. Along these lines, several hypotheses have been proposed to account for the reportedly higher prevalence of IgAN in Asian/Pacific Islanders. With respect to potential dietary antigens, Wakai et al. found that high intake of rice and n-6 polyunsaturated fatty acids (PUFA) were associated with an increased risk of IgAN . Recent iseases) ,23. WhetThe presence of either hypertension or proteinuria ≥ 3.0 g/24 hrs at the time of diagnosis significantly correlated with worsened renal survival in IgAN, even when controlling for serum creatinine at the time of kidney biopsy [Despite ongoing investigative efforts, scant data are available regarding genetic markers that may predispose individuals to progressive disease from IgAN. Recent immunogenetic studies have suggested a potential role for the T-cell receptor (TCR) in the development of immune-mediated diseases. Deenitchina and colleagues found that genetic polymorphism of the TCR constant alpha chain was associated with progression of CKD in a cohort of Japanese patients with IgAN. Although promising, such polymorphisms of the TCR gene have yet to be evaluated in large, prospective studies or by genetic analysis of familial IgAN .Our results contest the assertion that IgAN follows a more severe course in individuals of Asian/Pacific Islander descent. One reason for the similar disease severity of IgAN in our study population may stem in part from the large subpopulation of Filipino patients comprising our Asian/Pacific Islander cohort. It is unclear whether certain subpopulations of Asian/Pacific Islanders, including Filipinos, exhibit IgAN prevalence rates similar to those documented by Koyama and Woo. Anecdotal reports from Thailand and India documenting prevalence rates of 4–9% suggest that IgAN may not have the same epidemiology among all southeast Asians . DespiteThere are several important limitations to this report. As with any single-center biopsy series, we may have been underpowered to detect a clinically significant difference due to the limited sample size (type II error). In addition, racial admixture may have also confounded the results, as we were unable to subclassify patients in the Asian/Pacific Islander group or account for the growing population of bi- or multi-ethnic individuals in our population. Furthermore, due to the study's case control design, and breadth of our referral base , we were unable to control for the criteria for kidney biopsy. As a result, a biopsy bias may have confounded our results. In other words, Asian/Pacific Islander patients in our referral base with mild to moderate proteinuria and/or hematuria might have been given a presumptive diagnosis of IgAN without nephrology referral or confirmatory kidney biopsy. With regard to disease prevalence, these potential referral and biopsy biases based on race/ethnicity are largely conservative in nature, and would have biased our results towards the null. Finally, we have included data from a modest-sized IgAN transplant population N = 25), the donor demographics of which were unavailable at the time of the study. However, the association of race/ethnicity and distribution of glomerular lesion persisted, even when stratified by kidney transplant, and thus our overall conclusions remained the same. In addition, a small European study of donor-recipient pairs (average follow-up 7 years) has shown that when a donor kidney with asymptomatic IgA deposits is transplanted into a recipient with ESRD secondary to a disease other than IgAN, the IgA immune deposits in the donor kidney are rapidly removed [, the donIn conclusion, with the caveats of referral bias and biopsy bias, the race/ethnicity distribution of IgAN differs significantly from that of other major glomerulonephridities. However, among individuals undergoing native kidney biopsy, we see no evidence of a race/ethnicity association with severity of disease in IgAN by clinical and IgAN-specific histopathologic criteria. Further studies are needed to identify populations at higher risk for progressive disease in IgA nephropathy.None declared.YH designed the study, collected and analyzed the data, and drafted the manuscript. GC supervised the study design, analyzed the data, and edited the manuscript. EF graded the IgAN histopathologic slides. JO collected, reviewed and graded all histopathologic data, and edited the manuscript. All authors approved the final manuscript.The pre-publication history for this paper can be accessed here:


Hypertension is among the most common chronic condition in middle-aged and older adults. Approximately 50 million Americans are currently diagnosed with this condition, and more than $18.7 billion is spent on hypertension management, including $3.8 billion for medications. There are numerous pharmacological agents that can be chosen to treat hypertension by physicians in clinical practices. The purpose of this study was to assess the cost of alternative antihypertensive treatments in older adults with isolated systolic hypertension (ISH).Using the Systolic Hypertension in the Elderly Program (SHEP) and other data, a cost-minimization analysis was performed. The cost was presented as the cost of number-needed-to treat (NNT) of patients for 5 years to prevent one adverse event associated with cardiovascular disease (CVD).It was found that the cost of 5 year NNT to prevent one adverse CVD event ranged widely from $6,843 to $37,408 in older patients with ISH. The incremental cost of the 5 year NNT was lower to treat older patients in the very high CVD risk group relative to patients in the lower CVD risk group, ranging from $456 to $15,511. Compared to the cost of the 5 year NNT of other commonly prescribed antihypertensive drugs, the cost of SHEP-based therapy is the lowest. The incremental costs of the 5 year NNT would be higher if other agents were used, ranging from $6,372 to $38,667 to prevent one CVD event relative to SHEP-based drug therapy.Antihypertensive therapy that is diuretic-based and that includes either low-dose reserpine or atenolol is an effective and relatively inexpensive strategy to prevent cardiovascular events in older adults with isolated systolic hypertension. Use of the diuretic-based therapy is the most cost-effective in patients at high risk for developing cardiovascular disease. Hypertension is among the most common chronic conditions in middle-aged and older adults. Approximately 50 million Americans are currently diagnosed with this condition, and more than $18.7 billion is spent on hypertension management, including $3.8 billion for medications[Treatment of hypertension can significantly decrease the risk of developing CVD ,3. The SCurrently, primary care physicians can choose from numerous pharmacological agents to treat hypertension. The commonly used antihypertensive drug classes include diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, alpha-blockers, and calcium channel blockers. Selection of an evidence-based therapy with demonstrated efficacy, safety, and low cost has important economic implications. The purpose of this study was to: 1) assess cost of the SHEP-based antihypertensive treatment to prevent adverse events associated with CVD, including death, stroke, myocardial infarction, and heart failure; and 2) to compare cost of the SHEP-based treatment to the costs of other commonly used antihypertensive agent treatments.The SHEP trial is a randomized, double-blind, placebo-controlled clinical trial sponsored by the National Heart, Lung, and Blood Institute and the National Institute on Aging that tested the efficacy of diuretic-based stepped-care antihypertensive drug treatment of isolated systolic hypertension (ISH) to prevent strokes .The study subjects consisted of community-dwelling men and women 60 years and older who had isolated systolic hypertension, defined as an average systolic blood pressure (SBP) ≥ 160 mm Hg and an average diastolic blood pressure (DBP) < 90 mm Hg over 2 baseline visits. The primary endpoint of the trial was combined nonfatal and fatal stroke over a 5-year period. Secondary endpoints included nonfatal myocardial infarction (MI) plus fatal coronary heart disease (CHD) and major cardiovascular disease (CVD) morbidity and mortality. A total of 2,365 and 2,371 persons were randomized into the treatment and placebo group of the study respectively.4. Fasting blood samples were analyzed at a central laboratory, including serum glucose, lipid levels, creatinine, uric acid, sodium, and potassium.Subjects who met the preliminary blood pressure (BP) eligibility criteria at the initial contact visit were referred to SHEP clinics for the baseline visits. At the baseline visits, subject's demographics, medical conditions, health behaviors, and cardiovascular risk factors were obtained. Methods of these measurements have been reportedOf the 4,736 SHEP participants, 4,189 were included in this analysis. The 547 participants were excluded either because of missing data concerning CVD risk factors (n = 283) or with previous CHD or stroke (n = 264). These 547 excluded subjects had similar age, sex, race, and other characteristics as those who were included in this analysis.<160 mm Hg and for those with SBP between 160 and 179 mm Hg to have a reduction of at least 20 mm Hg. All participants were given chlorthalidone, 12.5 mg/d, or matching placebo (step 1 and dose 1 medication). Drug dosage (step 1 and dose 2 medication) was doubled, 25 mg/d, for participants failing to achieve the SBP goal at the follow-up visits. If the SBP goal was not reached at the maximal dose of step 1 medication, atenolol, 25 mg/d, or matching placebo was added (step 2 and dose 1 medication). When atenolol was contraindicated, reserpine, 0.05 mg/d, or matching placebo could be substituted. When required to reach the blood pressure goal, the dosage of the step 2 drug could be doubled . Potassium supplements were given to all participants who had serum concentration below 3.5 mm0l/L at two consecutive visits. The SHEP participants were followed up monthly until SBP reached the goal or until the maximum level of stepped-care treatment was reached [A stepped-care treatment approach was used, with the goal for individuals with SBP >180 mm Hg to reduce to  reached ,7The present analysis focused on five types of events: 1) death; 2) first-occurring major cardiovascular event, including stroke, MI, or heart failure; 3) first-occurring stroke; 4) first-occurring MI; and 5) first clinical diagnosis of congestive heart failure (CHF). The adjudication and clarification of the events was done by a panel of three physicians blinded to treatment assignment and blood pressure status. Members of the panel reviewed the documentation of new cardiovascular events over the study period and adjudicated outcome events according to predetermined criteria. [a priori global score for the risk of developing future cardiovascular events, according to the Multiple Risk Factor Assessment Equation jointly proposed by the American Heart Association and the American College of Cardiology.[Information at the baseline on age, sex, total cholesterol, high density lipid (HDL) cholesterol, systolic blood pressure, diabetes (diabetic vs. non-diabetic), and smoking (current vs. never or past smoking) were used to calculate an rdiology. The equaThe methods of economic evaluation include cost-effectiveness analysis, cost-utility analysis, and cost-benefit analysis, which can be used to assess the trade-off between costs and benefits in choices of antihypertensive treatment regimens. The primary aim of this analysis was to examine cost of the diuretic-based antihypertensive drug intervention in the SHEP trial. A cost-minimization analysis is a special type of cost-effectiveness analysis. It can be used to compare cost difference among competing alternatives of antihypertensive drug treatments when these treatments are medically equivalent. In this study, we used cost-minimization analyses to compare costs and incremental costs of NNT for 5 years to prevent one adverse event related to CVD among antihypertensive treatment regimens. The perspective of this economic evaluation was that of a national health insurance system.We used the number-needed-to-treat as an unit of common outcome measure in the analysis. The number-needed-to-treat to prevent one adverse outcome has become a widely used measure of treatment benefits derived from the results of clinical trials. The NNT is the reciprocal of the absolute risk reduction (ARR) which is the difference between the proportions with the adverse event in the treatment and placebo groups. The 95% confidence interval of NNT was calculated based on the regression-based method described by Laupacis et al. The cost specified in the analysis includes the drug acquisition cost of SHEP treatment from the perspective of a national health insurance system. According to the SHEP treatment protocol, the stepped-care was classified into four types of drug treatments: 1) the Step 1 and Dose 1: chlorthalidone 12.5 mg/d; 2) the Step and Dose 2: chlorthalidone 25 mg/d; 3) the Step 2 and Dose 1: chlorthalidone 25 mg/d plus atenolol 25 mg/d or reserpine 0.05 mg/d; and 4) the Step 2 and Dose 2: chlorthalidone 25 mg/d plus atenolol 50 mg/d or reserpine 0.1 mg/d. Direct drug acquisition costs were calculated based on the minimum average wholesale prices (AWP) within drug manufacturers in the year 2000. All drug1 × C1 + W2 × C2 + W3 × C3 + W4 × C4EC = WThe W1, W2, W3, and W4 represent proportions of the participants using the Step 1 and Dose 1, the Step 2 and Dose 2, the Step 2 and Dose 1, and the Step 2 and Dose 2 medication, respectively. C1, C2, C3, and C4 represent the drug acquisition cost of the Step 1 and Dose 1, the Step 2 and Dose 2, the Step 2 and Dose 1, and the Step 2 and Dose 2 medication, respectively. A Monte Carlo method was performed to estimate the average cost and its standard deviation.To compare the cost of the SHEP-based therapy to other antihypertensive drugs, it was assumed that all antihypertensive drugs in the comparisons have equal efficacy in terms of the NNT for 5 years to prevent one CVD related event. The NNT was calculated based on the method. All drug costs were expressed as dose-specific cost per patient in 1-year and/or 5-year. Using the approach, costs were calculated for each representative drug based on equipotent doses in terms of blood pressure reduction.  The non-In this analysis, we focused on the drug acquisition cost for antihypertensive management. Therefore, the monitoring cost for antihypertensive treatment was not included. Total treatment cost includes antihypertensive drug cost and monitoring cost. The monitoring of treatment in ambulatory care settings including physician visits and laboratory tests have an estimated cost of $284 per patient per year.  Total coTable Results of the 5 year NNT to prevent one adverse event and its associated cost by event type are shown in Table Table In Table The result of an economic evaluation essentially shows the cost per benefit gained from adapting a specific treatment. The effective and efficient use of resources has been increasingly emphasized from society, health plans, and health care providers. This cost-minimization analysis incorporating outcome data from the SHEP trial presents information treatment cost for older patients with ISH. We found that a long-term, low-dose and diuretic-based antihypertensive therapy is relatively inexpensive and effectively prevents adverse events associated with cardiovascular diseases, especially in older patients who had a high CVD risk profile.Our findings indicate that the total and incremental treatment costs of antihypertensive drugs in ambulatory care settings range widely among drug classes as well as within drug classes. This analysis suggests that diuretic-based antihypertensive treatments are the least expensive, whereas atenolol (beta-blocker) is less costly than enalapril (ACE inhibitor) and nifedipine , and terazosin  is the most expensive drugs in terms of the 5 year NNT to prevent one CVD event. It appears that use of the SHEP-based drug therapy offers greater economic benefits for controlling isolated systolic hypertension in the elderly than other antihypertensive drug treatments. Using a decision analysis model that simulated clinical decisions and outcomes that would occur when primary care physicians follow the JNC IV hypertension management guidelines, it was found that a newer class of calcium channel blockers can slightly increase the proportion of patients who achieve and maintain hypertension control, but at a substantially higher cost than with a generic diuretic drug. For our analyses, we presumed that all drugs offer equivalent therapeutic benefits. This assumption may have introduced a conservative bias into our primary findings. In fact, randomized controlled trials directly comparing active treatments for hypertension reported that calcium antagonists and doxazosin were inferior to low-dose diuretics or other agents in preventing cardiovascular events, suggesting that the cost-effectiveness of diuretic-based treatments may be even more favorable than estimated in the present study. -17 FurthWith regard to costs projected in our study, it is noteworthy to consider that compared to the SHEP treatments, costs of treatments based on more recently developed antihypertensive agents (than reported here) are likely to be even higher than estimated in the present analyses.The results of this study are limited to men and women 60 years and older who have isolated systolic hypertension and no presumed contraindication to any one class of antihypertensive medications. One limitation to our study relates to the fact that comparisons were based on costs of monotherapies, while combination therapies are frequently needed to control blood pressure.The number-needed-to-treat to prevent one adverse outcome has become a widely used measure of treatment benefits in medical community, which is easy for physicians to understand. The shortcomings of NNT are that the outcome measure of an effect is with one dimension- survival probability and that it measures the specified outcome at a single point in time. Therefore, a measure of NNT can not capture an outcome in effectiveness of the intervention with two dimensions: time and survival probability. These limitations may not allow us to take time and discounting on cost and effect into account in this study.Based on our findings, antihypertensive therapy that is diuretic-based and that includes either low-dose reserpine or atenolol represents a cost-effective regimen in preventing or delaying cardiovascular events in older adults. Use of the diuretic-based therapy is the most cost-effective in patients at high risk for developing cardiovascular disease. These results suggest that clinicians should consider using diuretics plus low-dose reserpine or atenolol as first-line therapy in patients with isolated systolic hypertension who are greater than 60 years old when there are no contraindications among these patients.ACE: angiotensin-converting enzymeALLHAT: Antihypertensive and Lipid Lowering treatment to prevent Heart Attack TrialARR: absolute risk reductionAWP: average wholesale priceBP: blood pressureCHD: coronary heart diseaseCHF: congestive heart failureCVD: cardiovascular diseaseDBP: diastolic blood pressureHDL: high density lipidISH: isolated systolic hypertensionJNC IV The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.NNT: number-needed to treatSBP: systolic blood pressureSHEP: Systolic Hypertension in the Elderly ProgramThe author(s) declare that they have no competing interests.GC, LF, WM and MP participated the development of the analytic framework. GC performed all data analyses. GC, LF, WM and MP drafted and revised the manuscript. All authors approved the final manuscript.


Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease. Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. It impairs the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol. Ezetimibe is an effective and safe agent for lowering LDL-C and non HDL-C. Short term clinical trials have established the role of ezetimibe monotherapy and its use in combination with statins. Furthermore, ezetimibe and statin combination therapy increased the percentage of patients who achieved their LDL-C treatment goal.Studies using surrogate markers of atherosclerosis have suggested a possible role of ezetimibe in combating atherosclerosis. Ezetimibe provides an effective therapeutic strategy for the management of homozygous familial hypercholesterolemia (HoFH) and sitosterolemia. The lack of outcomes and long term safety data is attributed to the relatively recent introduction of this medication. Over 60 million Americans suffer from cardiovascular disease (CHD). The incidence of CHD and stroke has been on the rise partly because of the increase in life expectancy and the explosive epidemic of diabetes and the metabolic syndrome . CHD is Animal and human studies have established the role of cholesterol in the development and progression of atherosclerosis. LDL-cholesterol (LDL-C) constitutes approximately 60–70 % of total serum cholesterol. Epidemiological studies directly implicated LDL-C to the development of atherosclerosis and CHD. Furthermore, LDL-C level appears to be directly related to the development and recurrence of CHD .Animal studies suggested a protective effect of low LDL-C against atherosclerosis . MultiplMost of the landmark CHD prevention trials involved the use of statin medications. LDL-C remains the primary target of treatment in most instances, and statins are the mainstay of LDL-C lowering treatment .The National Cholesterol Education Program/ Adult Treatment Panel III (NCEP/ATP III) updated guidelines table  for deteEzetimibe, a cholesterol absorption inhibitor, is the first agent of a new class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. Ezetimibe undergoes extensive glucuronidation to an active metabolite in the intestinal mucosa . EzetimiAfter oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide) , the druPlasma concentrations for total ezetimibe were about 2-fold higher in older individuals (>65 years), levels were similar in adolescents to healthy adults and may be higher in women than in men . In patiAdverse experiences were reported in approximately 2% of patients treated with ezetimibe and included fatigue, arthralgia, diarrhea, abdominal pain and back pain. Angioedema and rash were reported after general clinical use of this medication . With co1. Primary Hypercholesterolemia , Ezetimibe is indicated in this case for use as both mono and combination therapy.2. The reduction of elevated total-C and LDL-C levels in patients with homozygous familial hypercholesterolemia (HoFH) either as primary or as an adjunct to other lipid-lowering treatments.3. In patients suffering from Homozygous Sitosterolemia, as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.Multiple studies conducted to examine the effects of ezetimibe monotherapy have concluded that this drug was effective in lowering LDL-C versus placebo.Analysis of multicenter, double-blind, placebo-controlled trials demonstrated that ezetimibe at the 10 mg once daily clinically approved dose significantly modified cholesterol and cholesterol subtypes in patients with hypercholesterolemia when compared to placebo. Ezetimibe significantly lowered total-Cholesterol (TC) (12 %), LDL-C (18 %), apolipoprotein B (Apo B) (15 %), and triglycerides (TG) (7%) and increased high density lipoprotein (HDL-C) (3.5%) -24. LipoIn a case series report, we analyzed the effects of Ezetimibe on cholesterol particle size and number using NMR technology . We found that Ezetimibe lowered cholesterol particle number by a mean 26 % and had no significant effect on cholesterol particle size [The effects of ezetimibe on cholesterol and its subtypes were not influenced by risk-factor status, gender, age, race, time of administration, or baseline lipid profile . The oveThe struggle to achieve the NCEP/ATP III guidelines LDL-C goals through primary utilization of statins is often frustrating for the clinician. In a study to examine the efficacy of statin titration on attainment of LDL-C goal, the authors concluded that for high risk patients, approximately half were able to achieve their LDL-C goal at the appropriate statin starting dose, and only one third of the titration group were able to achieve the NCEP/ATP III cholesterol goal . Now witHMG-CoA reductase inhibitors (statins) act on the rate-limiting step to inhibit HMG-CoA conversion to mevalonate, effectively decreasing LDL-C synthesis. They result in a decrease of LDL-C ranging between 30–60 %, depending on the individual statin and the dose administered. Statin induced LDL-C lowering appears to be effective in reducing CHD and CHD related mortality and morbidity. The extent of CHD and CHD related events reduction is proportionate to the extent of LDL-C reduction ,28. LDL-Reasons to initiate combination therapy to treat hyperlipidemia include: further LDL-C lowering, reducing side effects related to higher doses of statins, modifying other risk factors besides LDL-C such as HDL-C and TG.Increasing the dose of statins has a limited effect on reducing LDL-C, as it is well established that doubling the dose of a statins leads to a 5 % more reduction in total TC and 7 % more reduction in LDL-C with each doubling .Although statins have demonstrated similarity in CHD related events, they are heterogeneous not only in LDL-C lowering efficacy but also in their safety profiles. The bulk of the statins effect on LDL-C occurs at the initial recommended dose and they are safer when used at doses below the maximal recommended dose.Statins are the most effective drugs known to modify LDL-C, but in terms of HDL-C and TG modifying capacity, other classes of lipid lowering medications used alone or in combination with statins offer higher efficacy.The metabolism of cholesterol is an intricate process that involves both produced and ingested cholesterol. The mechanism of action of HMG-CoA reductase inhibitors affects the production of cholesterol, whereas that of cholesterol absorption inhibitors affects absorbed cholesterol, thereby offering potential synergism of action when the medication are used in combination. Trials examining the efficacy have demonstrated synergism and consistency in LDL-C lowering in the absence pharmacokinetic interaction between the statins and ezetimibe.In a relatively large, multicenter study, involving patients with primary hypercholesterolemia already receiving statin monotherapy , patients were randomized to receive either ezetimibe or placebo in addition to their current statin therapy. At the conclusion of this 8 week study, the ezetimibe and statin groups were found to have a significantly lower total-C, LDL-C, Apo B, and TG, and increased HDL-C when compared to the statin only and placebo groups. Furthermore, LDL-C reductions induced by ezetimibe were generally consistent across all statins groups .Another multicenter, double-blind, randomized trial examined the effects of ezetimibe on patients suffering from (HoFH). At the initiation of the trial patients were receiving either atorvastatin or simvastatin. The addition of ezetimibe reduced LDL-C by an additional 20.5 % in contrast to only 6.7 % reduction that resulted from doubling the statin dose . SimilarThe addition of ezetimibe to statins is superior to treatment with statins alone in lowering non-HDL-C, ezetimibe co-administered with simvastatin lowered non-HDL-C by 47.1% whereas, simvastatin monotherapy lowered non-HDL-C by 33.6% when results were pooled across different doses [In terms of modifying risk factors other than LDL-C, the co-administration of ezetimibe with statins had a more favorable effect on HDL-C and TG when compared to statins therapy alone . In concEzetimibe co-administration with fibric acid derivatives was examined in a randomized, evaluator-blind, placebo-controlled, parallel-group study of 32 healthy hypereholesterolemics. Ezetimibe co-administration with fenofibrate was found to produce clinically significant reductions in LDL-C (36.3%) compared to the fenofibrate group (22.3%) with a more favorable TG and HDL-C profile .Sitosterolemia is a rare inherited disorder caused by mutation in either the ABCG5 or ABCG8 genes located on chromosome (2p21) . First dClinical manifestations include: tendon and tuberous xanthomas, episodes of hemolysis, accelerated atherosclerosis, and premature coronary artery disease. It is important to note that close to 50 % of these patients have normal cholesterol levels -41.A recently reported trial demonstrated that treatment with ezetimibe reduces plant sterol levels in patients with sitosterolemia. The authors reported a decrease in sitosterol concentrations by 21% and campesterol by 24 % .It is generally accepted that atherosclerosis is an inflammatory disorder. It is believed that the atherosclerotic process begins with endothelial cell activation, which is triggered by multiple factors such as oxidized lipoproteins. Cholesterol lowering agents as a group have demonstrated great efficacy in prevention and cessation of the progression of atherosclerosis. The efficacy of ezetimibe in monotherapy or in combination on CHD morbidity and mortality has not been well established.One of the unique features of cholesterol absorption inhibitors is their ability to modify post-prandial hyperlipidemia. There is increasing evidence that post-prandial lipoproteins (particularly cholesterol-rich chylomicron remnant) are atherogenic. Ezetimibe has the potential to reduce the cholesterol content of chylomicrons by up to 60% , which mHigh-sensitivity C-reactive protein (hs-CRP) is an inflammatory mediator whose levels correlate with increased coronary risk. Ezetimibe co-administered with simvastatin resulted in significant incremental decreases in hs-CRP in patients with primary hypercholesterolemia. Changes in individual lipid parameters did not explain the observed decreases in hs-CRP and were possibly consistent with an additional anti-inflammatory effect compared with simvastatin monotherapy .In a prospective trial to study effects of ezetimibe co-administered with atorvastatin in patients with primary hypercholesterolemia, ezetimibe plus atorvastatin significantly provided an additional (10%) lowering of hs-CRP versus atorvastatin alone .Ezetimibe and its class of cholesterol absorption inhibitors are new, and there is a lack of outcomes data to explore whether its cholesterol modifying effects will translate to lower CHD mortality and morbidity. The safety of this medication has not yet been established with long term trials data as most of the studies conducted were short term. With the advent and increased utilization of combination therapy in the management of dyslipidemia, further trials are needed to explore the efficacy, indications and safety profile of ezetimibe use in combination with Peroxisome proliferator-activated receptors (PPARs), niacin and bile acid resins.The increased popularity of special weight loss diets such as the high protein diet, poses questions of whether such diets will alter the efficacy or safety of cholesterol absorption inhibitors.Finally, the efficacy of statins in reducing CHD related events has lead to the controversial hypothesis regarding whether or not statins poses a pleiotropic (non lipoprotein) effect. If a pleiotropic effect exists, one might argue that a statin at a higher dose might be more beneficial than combination therapy producing the same effect.Ezetimibe is the first clinically approved cholesterol absorption inhibitor. It is effective in lowering LDL-C as monotherapy or in combination with statins. The use of combination LDL-C lowering medication is expected to become a much more common modality of treatment, especially after the recent NCEP/ATP III update. Ezetimibe offers further lowering of LDL-C and non HDL-C that is consistent and probably safer than increasing the dose of the individual statin. It also provides another effective treatment option for HoFH and sitosterolemia patients. Because of its recent introduction, we still lack both outcomes and long term safety data.


Dyslipidemia has been associated with hypertension. The present study explored if polymorphisms in genes encoding proteins in lipid metabolism could be used as predictors for the individual response to antihypertensive treatment.1-adrenergic receptor blocker atenolol for twelve weeks.Ten single nucleotide polymorphisms (SNP) in genes related to lipid metabolism were analysed by a microarray based minisequencing system in DNA samples from ninety-seven hypertensive subjects randomised to treatment with either 150 mg of the angiotensin II type 1 receptor blocker irbesartan or 50 mg of the βThe reduction in blood pressure was similar in both treatment groups. The SNP C711T in the apolipoprotein B gene was associated with the blood pressure response to irbesartan with an average reduction of 19 mmHg in the individuals carrying the C-allele, but not to atenolol. The C16730T polymorphism in the low density lipoprotein receptor gene predicted the change in systolic blood pressure in the atenolol group with an average reduction of 14 mmHg in the individuals carrying the C-allele.Polymorphisms in genes encoding proteins in the lipid metabolism are associated with the response to antihypertensive treatment in a drug specific pattern. These results highlight the potential use of pharmacogenetics as a guide for individualised antihypertensive treatment, and also the role of lipids in blood pressure control. Hypertension is a complex trait caused by multiple environmental and genetic factors interacting through the cardiac, vascular and endothelial systems. Several drug classes with different mechanisms of action, including inhibitors of the renin-angiotensin-aldosterone system (RAAS), calcium channel blockers, adrenergic receptor blockers and diuretics, are available for treatment of hypertension. However, the response to antihypertensive treatment is highly variable between individuals, which makes it difficult to predict the efficacy of a specific drug in the individual patient -3. CurreTwin studies have estimated that as much as half of the variability in blood pressure levels between individuals is due to genetic factors ,8. Based1-adrenergic receptor blocker atenolol [The RAAS and the sympathetic nervous system play key roles in blood pressure regulation. We have earlier shown that polymorphisms in the angiotensin converting enzyme gene  and a SNatenolol . DyslipiWe have recently developed a microarray based minisequencing system for parallel genotyping of multiple SNPs in blood pressure regulating candidate genes . Here we1-adrenergic receptor blocker atenolol once daily as monotherapy. The dose was doubled after six weeks if the diastolic blood pressure was ≥ 90 mmHg. Blood pressure was measured by trained nurses using a mercury sphygmomanometer, after the patients had rested for at least 10 min in the seated position. Left ventricular hypertrophy was defined as left ventricular mass index of > 131 g/m2 for men and > 100 g/m2 for women, assessed by echocardiography. The data presented relates to the change in blood pressure after 12 weeks of treatment. For details on the SILVHIA trial, see Malmqvist etal [DNA extracted from blood samples from 97 hypertensive patients from the double blind parallel group "Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol" (SILVHIA) trial  were anaist etal . Baselin) and the SNP Consortium  databases and validated in a pooled DNA sample representing the Swedish population. A subset of these SNPs located in genes involved in lipid metabolism and that were polymorphic in the Swedish population were included in the study presented here, together with one additional SNP in the apolipoprotein A-V gene. See Table In our previous study , 98 SNPsFragments comprising the SNPs were amplified in multiplex PCR described previously . A microAnalysis of covariance (ANCOVA) with each SNP as factor, baseline blood pressure as covariate and the change in blood pressure as response, was performed. The analyses were performed by treatment group and blood pressure measurement (systolic and diastolic blood pressures). Correction for multiple testing was performed by calculation of critical p-values corresponding to a nominal type I error of 5% using a permutation test . Two taiWe explored possible associations between individual genotypes of ten SNPs and reduction in systolic and diastolic blood pressure as response to treatment with atenolol or irbesartan Figure  in samplCorrection for multiple testing using a permutation test  yielded The SNP C711T in the apolipoprotein B gene is located in the coding region of the gene, and alters a threonine residue to an isoleucine residue in the protein. This SNP is located in the amino-terminal part of the enzyme and has been suggested to affect the dimerisation of apolipoprotein B and low density lipoprotein during cholesterol transport . The C16We have recently found circulating apolipoprotein B to be the most powerful predictor of endothelium-dependent vasodilation of the commonly used markers of cholesterol metabolism . It is nIn our earlier exploratory study, 74 SNPs with a minor allele frequency over 5%, including nine of the SNPs analysed here were tested as predictors of blood pressure regulation in the SILVHIA study samples using a multiple regression model . The maiA remaining weakness in our study is the small number of samples available for analysis, which does not allow detection of small to medium size gene effects, and results in uncertain estimation of the the magnitude of the effects detected. Moreover, in a small study there is the risk of a non-representative group of patients with respect to gender, age, and genotype distribution. Despite these limitations, we detected a significant effect of the SNP C711T in the apolipoprotein B gene and the SNP C16730T in the low density lipoprotein receptor after correction for multiple testing. The pharmacogenetically interesting results from our study need to be replicated in other studies.As the C711T SNP in the apolipoprotein B gene predicted response to treatment with irbesartan, and the C16730T SNP in the low density lipoprotein receptor gene appeared to predict response to atenolol treatment, our results point at possible use of SNPs in genes encoding components of lipid metabolism in pharmacogenetic panels for selecting the optimal drug for each patient. To our knowledge our study is the first one to investigate the relationship between polymorphisms in genes involved in lipid metabolism and the response to antihypertensive treatment.The authors declare that they have no competing interests.UL performed the development of genotyping technology, genotyping lab work, interpretation of data and had a substantial role in writing the manuscript. LL provided clinical expertise, participated in selection of candidate genes and contributed to writing. LK provided clinical expertise, established a database of the SILVHIA phenotypes, and in writing. LB performed the statistical analysis. TK provided the SILVHIA samples and contributed to writing the manuscript. A-CS contributed by planning and supervision of the project, and to writing the manuscript.The pre-publication history for this paper can be accessed here:


Hypertension is a growing worldwide problem associated with an increased risk of cardiovascular morbidity and mortality. However, the rates of prevalence of hypertension are higher in some populations than others. Although ethnic and genetic factors have been implied in the past to explain this, the environmental influence and psychosocial factors may play a more important role than is widely accepted. Examining the non-genetic influences in future hypertension research may be necessary in order to clearly define the local blood pressure demographics and the global hypertensive disease burden. Hypertension is a common problem, with a consistent and continuous risk of cardiovascular disease and stroke associated with rising blood pressure levels . FurtherThe consequences of poor blood pressure control are huge. As high blood pressure is the most important risk factor for cardiovascular disease, it has been calculated that by achieving the target of 140 mmHg, there would be a reduction of 28–44% in stroke and 20–35% in ischaemic heart disease depending on the age. This would prevent approximately 21400 stroke deaths and 41400 ischaemic heart disease deaths each year – and these translate to approximately 42800 strokes and 82800 ischaemic heart diseases saved, making a total of 125600 events saved per year in the United Kingdom alone [Nonetheless, what is more intriguing and perhaps still not fully explained, is why some populations seem to have a much higher population prevalence of hypertension as compared to others. For instance, the prevalence and incidence of hypertension differs between the non-westernised and westernised populations. Even within the western world, the Afro-Caribbean or African-American black population has a higher prevalence of hypertension and target organ damage related to it, as compared to white Europeans or Americans . DiffereBMC Medicine, address the issue of whether there is a truly genetic predisposition or perhaps an environmental influence is to blame for higher rates of prevalence of hypertension seen in some of these ethnic populations. In a well-designed pooled analysis, incorporating eight studies involving 8 white and 3 black populations from the North American, European and African populations – a dataset of nearly 85,000 patients – Cooper et al [Cooper et al , writinger et al  examinedper se together with the unhealthy lifestyle and diet in the western world increase the risk of hypertension, compared to the rural, 'low stress', healthier lifestyle and dietary habits in Africa? Perhaps the genotype of black subjects was not idealised for the 'pro-hypertension' environment of the western world, leading to the greater risk of developing hypertension amongst blacks in the western world. This 'genetic predisposition' of certain ethnic groups, coupled with the 'wrong' environment, leads to an unhealthy combination that predisposes to cardiovascular disease [Does this take us back to the drawing board? Perhaps environmental factors do play a more major role in developing hypertension than is widely accepted. Indeed, does urbanisation  disease . However disease . Therefo disease . SimilarCan this 'wrong genotype in the wrong environment' hypothesis be applied to hypertension in black African-Americans? Efforts have already been made to understand the reasons behind the higher prevalence of hypertension in African Americans, with the underlying assumption that there may a genetically determined predisposition as compared to their white counterparts; however, no convincing data are available . This maNumerous potential explanations for the higher prevalence of hypertension in blacks have been proposed. Genetic mechanisms have been used to explain familial aggregation of hypertension in Jamaican blacks and the intra-class correlation of systolic blood pressures amongst black twins ,14. Low Notwithstanding the shortcomings of a retrospective, pooled study, with varying criteria for inclusion, and the intra-, inter- and cross-study observational errors, Cooper et al  have shoEvidence that environmental and particularly psychosocial factors are important in the development of hypertension also comes from a series of epidemiological studies conducted in the early part of the last century, which have shown that urbanisation and adoption of a westernised life style leads to blood pressure rises. Many of these studies have been conducted in Africa, where the rural populace has a relatively low prevalence of hypertension. For example, primitive black populations living in more frugal circumstances in rural Africa have been shown to have low blood pressures. Evidence suggests that there are some populations that exist who are naïve to hypertension and related morbidity. Interestingly, their blood pressures hardly rise with increasing age, a common response to age in many other (urbanised?) communities -18. The Migration, not withstanding the complexity of the studies in these populations, has been shown to significantly affect blood pressures. A study examining the migrant islanders into New Zealand showed raised population blood pressures, as well as an increased slope of the age-blood pressure relationship . The KenThe issue of the influence of colour of the skin to blood pressures is even more complex. On the one hand, studies in America have shown relationship between the dark skin and blood pressures, leading to some suggesting that the link is genetic. In contrast, some argue that it is a manifestation of the stress and social pressure of having a dark skin that causes this. In Cuba, for example, where communist principles are considered to have broken the racial barriers, the ethnic differences in blood pressures were shown to be small, supporting the latter argument . In addiThus, the process by which a society becomes more economically advanced or "developed" seems to be associated closely with rates of hypertension prevalence. Indeed, lifestyle and dietary changes related to the so-called "development" seem linked to the prevalence of hypertension. In the INTERHEART population case-control study , which wThere remain many uncertainties to the relative importance and contribution of environmental versus genetic influences on the development of blood pressure – there is more than likely an influence from both. However, there is now evidence to necessitate increased attention in examining the non-genetic influences on blood pressure, a neglected area of hypertensive research but perhaps a goldmine for establishing causal influences. As stated earlier, the future of hypertension research should focus on more standardised and comparable protocols, with comparable designs in data collection. Multi-centric data collection with a view to establishing local or national blood pressure demographics is crucial for the formal assessment of the global hypertension burden and the implementation of cost-effective primary preventive measures.The pre-publication history for this paper can be accessed here:


Multiple studies have linked fungal exposure to asthma, but the link to severe asthma is controversial. We studied the relationship between asthma severity and immediate type hypersensitivity to mold  and non-mold allergens in 181 asthmatic subjects.Aspergillus, Alternaria, Cladosporium, Penicillium and Candida) and 4 other common inhalant allergens .We recruited asthma patients aged 16 to 60 years at a University hospital and a nearby General Practice. Patients were categorized according to the lifetime number of hospital admissions for asthma . All subjects had allergy skin prick tests performed for 5 mold allergens . Multiple mold reactions were also much commoner in the group with multiple admissions . The number of asthma admissions was related to the number and size of positive mold skin allergy tests  and less strongly correlated to the number and size of non-mold allergy tests . Hospital admissions for asthma patients aged 16–40 were commonest during the mold spore season (July to October) whereas admissions of patients aged above 40 peaked in November-February .Skin reactivity to all allergens was commonest in the group with multiple admissions. This trend was strongest for mold allergens and dog allergen and weakest for These findings support previous suggestions that mold sensitization may be associated with severe asthma attacks requiring hospital admission. Alternaria species has been reported to be especially common in patients with life-threatening asthma [Most asthma patients have mild symptoms which are well controlled with anti-inflammatory and bronchodilator therapy but a minority of asthma patients have severe airway inflammation and airflow obstruction requiring multiple hospital admissions. The reasons for these differences in asthma severity are complex and not fully understood . At leasg asthma . Asthma g asthma -11. Moldg asthma -17.Indoor mold exposure might also contribute to asthma severity. Many patients believe that their asthma is aggravated by damp housing, especially if there is visible mold growth . It has These studies prompted us to undertake a study of asthmatic patients in Salford in Greater Manchester (North-West England) to assess whether atopy in general and mold sensitization in particular was associated with increased asthma severity. There are few agreed definitions of severe asthma so we used hospital admissions and treatment category (according to British Thoracic Society Asthma Guidelines) as surrogate markers for asthma severity .This study was undertaken in Hope Hospital, a 900 bedded University Hospital in Salford, Greater Manchester, UK. The study was designed to record the atopic status for mold and non-mold allergens of asthma patients at every level of severity from very mild to very severe . We studied patients with severe asthma during hospital admissions or at subsequent visits to the hospital chest clinic. Patients were recruited opportunistically during hospital admissions or during routine consultations with the Respiratory Nurse Specialist (RNS) in the hospital Chest Clinic. Recruitment was evenly spread over 30 months from January 1996 to June 1998. During this period, the Respiratory Nurse service was under development with only one part-time RNS available to serve a large population of hospital in-patients and ambulatory care patients at chest clinics. Ward-based doctors and nurses referred patients with acute asthma to the RNS on an opportunistic basis based on availability of the part-time RNS and whether the ward teams were aware of the developing RNS service. About 20% of all adult asthma patients admitted during the study period were referred to the RNS and most of these were recruited in the study (provided the RNS had time available to do so). Although recruitment was not systematic (based mainly on availability of RNS service), we were not aware of any potential bias which might have affected the recruitment process and we believe that the recruited patients were typical of adult patients with acute asthma admitted to our hospital. We recruited ambulatory patients  at the same hospital chest clinic and in a single Primary Care practice where 25 patients were recruited during routine consultations with the practice nurse. This recruitment was also opportunistic, based mainly on the availability of time to complete the study protocol during busy clinics. We believe that these patients were typical of patients seen at hospital chest clinics and General Practice asthma clinics in this area. Patients were grouped according to their lifetime history of hospital admissions for asthma . Patients with no hospital admissions were further categorized according to the treatment steps described in the British Thoracic Society guidelines for asthma management; Step 1 requiring only occasional bronchodilator treatment, Step 2 requiring low-doses (<800 mcg per day) of inhaled steroid, Step 3 requiring high doses of inhaled steroids or long acting beta agonists, Step 4 requiring additional therapy such as domiciliary nebulized therapy . We atteAll patients were Caucasians who were lifelong residents of the United Kingdom. Inclusion criteria were a diagnosis of asthma by the patient's doctor, age 16 to 60 and ability to give informed consent. All subjects gave written informed consent prior to partaking in the study which was approved by the Salford Research Ethics Committee. Exclusion criteria included a diagnosis of COPD, non-European ethnic group  and consumption of any antihistamine in the previous 48 hours. All subjects completed a questionnaire concerning respiratory symptoms, smoking status and allergies.Dermatophagoides pteronyssinus, cat, dog, mixed grass pollen, Aspergillus fumigatus, Alternaria alternata, Cladosporium herbarum, Penicillium notatum and Candida albicans.All tests were conducted by one author (LCH) or by one other respiratory nurse specialist using a standardized technique in an open manner. A small drop of allergen was placed on the volar surface of the forearm. Allergens were purchased from Allergopharma , a single batch of each allergen was used throughout the study. We used skin test lancets with a 1 mm tip . The lancet was introduced vertically into the skin through the allergen solution. Allergens studied were: negative control, histamine 0.1%, Aspergillus and a 5 mm reaction to Cladosporium would have a "mold sensitization score" of (6-1)+(5-1) = 9 mm.Weal diameter (if any) was recorded at 15 minutes. If a weal was asymmetrical, the mean of two perpendicular measurements was calculated. Weals less than 3 mm greater than the negative control reaction were regarded as negative in accordance with guidance issued by the European Academy of Allergology . We deviAs a subsidiary study , we also studied the seasonality of asthma admissions in Salford by reviewing the electronic records of 520 asthma admissions under the care of two pulmonary physicians who kept a computerized database at this hospital between 1995 and June 2000 . This covered a wide time-span before, during and after the period of the mold sensitization study; some of the allergy study patients were admitted and recruited during this time but they represented only a small (and random) proportion of the admissions studied for seasonality. Asthma admissions were analyzed by month of admission and divided into 3 four-month "seasons"; March to June ; November to February ; . PatientStatistical analysis was performed using Prism II software . Chi squared test was used to compare the number of positive allergy skin tests between groups of asthma patients. Spearman Correlation Coefficient was used to compare each patients lifetime number of hospital admissions with their "Mold sensitization score" (as described above). Mann Whitney tests were used to compare mean sensitization scores between groups of patients.One hundred eighty-one asthmatic patients were recruited. Their characteristics are given in table Positive skin tests to all allergens were commoner in the group with severe asthma  than patients with milder asthma. Table . Atopic Alternaria) to 41% (Cladosporium) in the severe asthma group compared with 0–10% in the milder asthma groups.Mold sensitization was uncommon in mild asthma but very common in asthma patients with multiple admissions Figure . There wAspergillus and Candida precipitins and specific IgE were not measured in this study. None of these patients had any clinical features suggestive of allergic bronchopulmonary aspergillosis (ABPA) such as pulmonary infiltrates, bronchiectasis or marked eosinophilia. The number of admissions correlated with the number and size of positive skin tests using the scoring system described previously. For mold sensitization, the Spearman Correlation Coefficient was 0.60 (two-tailed p < 0.0001) and for non-mold allergens was 0.34 (two-tailed p = 0.0005). The cumulative "mold sensitization score" and the "non-mold sensitization score" for each group of patients is shown in table Aspergillus, one Penicillium).Of the patients not admitted to hospital, 32 had very mild asthma (BTS Step 1), 25 had mild-moderate asthma (BTS Step 2) and 25 had moderate to severe asthma (BTS Steps 3–4). There was no significant difference in mold or non-mold sensitization between these groups of non-admitted patients with different grades of asthma severity.Our review of asthma admissions to this hospital between 1995 and 2000 identified 520 patients admitted under the care of the two chest physicians who kept a computerized database . There were 173 asthma admissions in the 16–40 age group, these admissions peaked in late summer and fall (figure Alternaria or Cladosporium is a powerful risk factor for severe asthma[D. pteronyssinus) sensitization in our patients with more severe asthma [Although the present study was larger than most previous studies of mold sensitization in severe asthma, it must be regarded as a "pilot study" due to the non-systematic recruitment of asthma patients and the cross-sectional nature of the study. Our data indicate that mold (and dog) sensitization is common in patients with severe asthma requiring multiple hospital admissions in Manchester. The results are consistent with previous evidence that atopy  is related to asthma severity or bronchial hyper-reactivity -6,12-17.re asthma in severre asthma,14. We he asthma ,25. HoweThere has been some debate about the best cut-off point for weal size to define a positive skin-prick test. We accepted the European Academy of Allergology figure of 3 mm greater than the negative control . HoweverA key question is whether severe asthma is actually caused by sensitivity to molds or is simply associated with it. In any case, mold sensitivity will certainly not be the only cause of severe attacks of asthma; upper respiratory tract virus infections and some drugs being two of other well documented causes. The greater degree of mold sensitization in the severe asthma group could simply reflect an extreme example of the generalized increase in atopy amongst this group. However, we believe that mold allergy may be responsible for severe asthma attacks for several reasons.Alternaria-sensitive had their near-fatal asthma episodes in summer and early fall when mold spore levels would be expected to be high [First, the temporal relationship between high environmental spore counts and asthmatic attacks is strong. Airborne spore levels may be up to 1000 times higher than pollen levels . The dat be high .Cladosporium in July, Alternaria and hyaline basidiospores in August, uredospores in September and coloured basidiospores in October. The data from Derby (52 miles south-east of Manchester) are similar[Cladosporium, Alternaria, Penicillium and Aspergillus with maximal levels between June and October [A. alternata and C. herbarium was common and associated with asthma severity – OR of 2.03 for the former, of 3.2 for the latter fungus and 2.34 for both. No such association was found for pollens or cats, although sensitization to house dust mite was slightly more frequent in those with severe asthma (OR 1.61) [Second, the seasonal  peak of asthma admissions occurs when ambient air counts of molds are high. We have documented a late summer-fall peak of asthma admissions involving young adults in Manchester which coincides with the summer-fall peak of asthma deaths in UK patients aged under 35 years ,21. These similar. In addi October . A pan-E October . SensitiOR 1.61) . The preThird, there is evidence that indoor mold exposure may contribute to asthma severity. Many patients report respiratory symptoms in damp and moldy houses and a review of nine population-based studies found that seven reported one or more positive associations between fungal levels and health outcomes . The stuAspergillus in particular is a major respiratory allergen causing the vast majority of cases of allergic bronchopulmonary mycosis [Aspergillus and Candida allergens may share IgE-binding epitopes [Aspergillus and a few other common airborne fungi have and it is likely that sensitization to other fungi will be discovered in the future.Fourth, we know that  mycosis -33. It iepitopes . Howeverepitopes . Few funCandida is present in the gut of most, if not all, humans. The difference may relate to the nature or intensity of exposure to mold allergens or to their ability to become airborne and to gain entry to human airways due to their small size. Also many potent allergenic proteins have been described in Aspergillus and some in other fungi [Aspergillus is inhaled, which is almost hourly. Some fungal antigens are proteases  and as DP1 is also a protease – a similar pathogenic role can be postulated [It is not known why mold allergens should produce more severe airway disease than other common allergens such as house dust mites, cat dander, or grass pollen. Fungi are very common in the environment and er fungi . There istulated ,36.It therefore seems likely that there is a causal relationship between mold allergy and asthma severity for some younger asthma patients. Our seasonal admissions data suggest that up to 6% of adult asthma admissions in Manchester and 19% of asthma admissions in the 16–40 age group may be attributable to mold allergy. These unlucky individuals seem to have more severe asthma than patients with sensitization to other common allergens and an increased risk of fatal or near-fatal asthma or hospital admissions during the mold spore season, especially on days when the local mold spore count is high. The risk may be further increased if the patient lives in a damp, moldy house or attends a damp moldy school ,30,37. ICandida albicans, is a yeast, does not become airborne but does produce hyphae in tissue. Thus it is possible that human asthma due to fungal allergens may have three sources of allergen exposure – outdoor mold spores, indoor mold spores and endogenous fungal growth on body surfaces including the skin and gut [One of the fungi which we investigated and for which antigenic extracts are available,  and gut .Alternaria sensitization in Italian patients with respiratory symptoms ranges from 2% in Northern Italy to 29% in Southern Italy [Fungal sensitization is relatively uncommon in our British asthma patients and in Finnish schoolchildren  comparedrn Italy . Some ofrn Italy . Also furn Italy ,16,17 suThe findings of this study support previous suggestions that mold sensitization may be associated with severe asthma attacks requiring hospital admission.BTS Guidelines = British Thoracic Society Guidelines for Asthma Management, RNS = Respiratory Nurse SpecialistThe author(s) declare that they have no competing interests.ROD originated and co-ordinated the study and contributed to the analysis of the data and preparation of the paper.LCH contributed to the design of the study and was the main clinical investigator. She also contributed to the analysis of the data and preparation of the paper.DWD contributed to the design of the study and contributed to the analysis of the data and preparation of the paper.The pre-publication history for this paper can be accessed here: