Use Of Angiotensin II Receptor Blockers Research Articles

PP.01.28

Objective: 1. To identify the percent of prescription of angiotensin-convertin enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in a cohort of patients admitted for acute coronary syndrome (ACS). 2. To study the determinants related with a under use of ACEI and ARB in a local cohort of acute coronary syndrome. Design and method: From January 2012 to January 2013, we enrolled all patients with ACS discharged from two hospitals of our site. Patients with intolerance o allergy to ACEI or ARB were excluded. To identify determinants of ACEI and ARB under use we performed a multivariate logistic regression analysis. Results: 641 patients were included (68 years means; 73.5% males). Of them, 559 (87%) received ACEI or ARB at discharge, with higher prescription of ACEI (56%) than ARB (31%). Patients who received these drugs were older (68 [62–86] vs 61 [54–73];p = 0,001) and had more cardiovascular risk factors like hypertension (80%(444) vs 52%(43);p < 0,001) and Diabetes Mellitus (48%(266) vs 26%(21);p < 0.001);reduced left ventricular ejection fraction (LVEF < 50%) (31,5%(168) vs 10,8% (8);p < 0,001), previous STEMI (14,3% (80) vs 6% (5);p = 0,04) and treatment with beta-blockers at discharge (95%(531) vs 87%(71);p = 0,01). After multivariate adjustment, preserved LVEF (>50%), abscense of hypertension and Diabetes Mellitus and not prescription of beta-blockers at discharge were identified as the independient predictors of under use of ACEI and ARB. Conclusions: 1a. There is a high use of ACEI and ARB at discharge after acute coronary syndrome, according to current clinical guidelines. 2a Determinants of underuse of ACEI and ARB were: preserved LVEF (>50%), the abscence of hypertension and Diabetes Mellitus; and not receive beta-blockers at discharge.

Hyperkalemia Develops in Some Thyroidectomized Patients Undergoing Thyroid Hormone Withdrawal in Preparation for Radioactive Iodine Ablation for Thyroid Carcinoma

Hyponatremia is observed in hypothyroidism, but it is not known if hypo- or hyperkalemia is associated with hypothyroidism. To study these questions, we determined serum potassium (K(+)) levels in thyroidectomized patients undergoing levothyroxine withdrawal before radioactive iodine (RAI) therapy for thyroid carcinoma. We retrospectively studied the records of 108 patients who had undergone total thyroidectomy for thyroid carcinoma followed by levothyroxine withdrawal and then ablation with RAI at Nagasaki University Hospital from 2009-2013. Blood samples were analyzed for serum K(+) concentrations when patients were euthyroid just before levothyroxine withdrawal and hypothyroid 21 days after levothyroxine withdrawal. We determined the proportion of patients who developed hyperkalemia (K(+) ≥5 mEq/L) and hypokalemia (K(+) ≤3.5 mEq/L). Five (4.6%) patients developed hyperkalemia and 2 (1.9%) patients developed hypokalemia after levothyroxine withdrawal. The mean serum K(+) level after levothyroxine withdrawal was significantly higher than before levothyroxine withdrawal (4.23 ± 0.50 mEq/L vs. 4.09 ± 0.34 mEq/L; P<.001). After levothyroxine withdrawal, serum K(+) values were significantly correlated with age, serum sodium and creatinine levels, and the estimated glomerular filtration rate but not with serum free thyroxine or thyroid-stimulating hormone concentrations. The finding of an elevated serum K(+) of >0.5 mEq/L after levothyroxine withdrawal was more prevalent with age >60 years (odds ratio [OR], 4.66; P = .026) and with the use of angiotensin-II receptor blockers or angiotensin-converting enzyme inhibitors (OR, 3.53; P = .033) in a multivariate analysis. Hyperkalemia develops in a small percentage of hypothyroid patients after thyroid hormone withdrawal, especially in patients over 60 years of age who are using antihypertensive agents that inhibit the reninangiotensin-aldosterone system.

Factors affecting albuminuria in diabetic patients at King Fahad Hospital in Almadinah Almunawwarah

Abstract Objective To identify factors associated with development of albuminuria in diabetic patients. Methods A hospital based case–control study. Fifty diabetic nephropathy patients were compared with 100 diabetic patients without nephropathy. Data were collected using an interview questionnaire. Frequencies, percentages and mean were calculated. Chi-square test, T -test and Univariate logistic regression analysis were used. P Results An Univariate logistic regression analysis has shown significant associated factors including old age (OR = 8.1) (95%CI = 2.2–30.1), sex (male) (OR = 2.4) (95%CI = 1.18–4.99), the duration of diabetes mellitus above 10 years OR were 4.23 (95%C = 1.6–15.4), associated mild, moderate, and severe hypertension ORs were 5.2 (95%CI = 2.3–11.7), 5.1 (95%CI = 1.5–16.93) and 15.2 (95%CI = 1.4–158.1), respectively, cardiac disease (OR = 3.77) (95%CI = 1.6–8.7), using Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs) (OR = 8.1) (95% CI = 3.61–18.2), low triglyceride level (OR = 0.38) (95%CI = 0.10–0.81). Conclusion Six factors showed a significant positive relationship to the progression of albuminuria in diabetic patients. Older age and males were found to be predictors of high albuminuria. Also, cardiac disease, poor hypertension control, the use of ACEIs or ARBs were found to be predictors of higher albuminuria. Low triglyceride levels were significantly associated with low albuminuria. Higher levels of HbA1c showed less albuminuria while body mass index, smoking and retinopathy showed no association to the albuminuria.

Risk of Osteoporotic Fractures With Angiotensin II Receptor Blockers Versus Angiotensin-Converting Enzyme Inhibitors in Hypertensive Community-Dwelling Elderly

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are used to treat hypertension; however, in vivo and clinical studies suggest that ARBs and ACE inhibitors may exert different effects on bone. The association between long-term use of ARBs and ACE inhibitors and fracture requiring medical attention is limited. We conducted a population-based, retrospective cohort study with propensity score matching using administrative databases in Ontario, Canada, to examine the risk of osteoporosis-related fractures in hypertensive elderly treated with ARBs versus ACE inhibitors. We identified a cohort of newly treated hypertensive patients aged 66 years and older who initiated an ACE inhibitor from May 1, 2004, to March 31, 2012, and matched them to ARB users on propensity score, sex, and age at drug initiation. The primary outcome was hip fracture, and secondary outcomes were non-hip major osteoporotic fractures (other femoral, clinical vertebral, forearm, wrist, humerus) and other osteoporotic fractures (pelvis, clavicle, patella, shoulder, upper arm, tibia, fibula, ankle, scapula, ribs, sternum, trunk). We calculated hazard ratios (HRs) using Cox proportional hazards model with robust standard errors. Of the 87,635 patients who initiated treatment, 28,819 (32.9%) started ARBs and 58,816 (67.1%) started ACE inhibitors. Among new ARB users, 27,815 (96.5%) were successfully matched to ACE inhibitor users. Without dose adjustment, no significant association was observed for ARBs relative to ACE inhibitor users for hip fractures (HR = 0.88; 95% confidence interval [CI] 0.70-1.11), with a decreased risk of other major osteoporotic fractures (HR = 0.81; CI 0.70-0.93) and no significant association for other osteoporotic fractures (HR = 0.88; CI 0.74-1.05). When adjusted for dosage, there was no significant difference between the effects of ARBs and ACE inhibitors on hip (HR = 0.99; CI 0.78-1.25), other major osteoporotic (HR = 0.87; CI 0.75-1.01), and other osteoporotic fractures (HR = 0.90; CI 0.74-1.08).

Relative lymphocyte count as a marker of progression of chronic kidney disease

Although low relative lymphocyte count (RLC) is associated with poor outcomes in patients with chronic kidney disease (CKD), the relationship between low RLC and progression of CKD is poorly defined. The aim of this study was to determine the association between low RLC and the progression of CKD. Between January 2003 and December 2009, 288 CKD patients were analyzed. RLC was calculated as the ratio between lymphocyte and total white blood cell counts. The median RLC was 29.1% [interquartile range (IQR) 24.1-34.1]. When the patients were compared according to a level below or above the median value for RLC, the rate of CKD progression to end-stage renal disease (ESRD) was greater in patients with low RLC count than in patients with high RLC (48 vs. 25%, p < 0.001) during the median follow-up of 5.5 years (IQR 3.5-7.6). The variables found to be predictive of progression to the ESRD included younger age, smoking, diabetes, higher systolic blood pressure, no use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), lower hemoglobin and serum albumin levels, higher low-density lipoprotein cholesterol concentration, presence of proteinuria, and low RLC in the univariate Cox proportional hazards regression analysis. However, after adjustment, younger age, male, higher systolic blood pressure, no use of ACEIs or ARBs, lower hemoglobin and serum albumin concentrations, higher proteinuria, and lower RLC were significantly associated with progression to ESRD in multivariate analysis. Low RLC is independently associated with increased rate of progression in patients with CKD.

Renin-angiotensin system antagonists and clinical outcomes in stable coronary artery disease without heart failure

The aim of this study was to determine whether angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-II receptor blocker (ARB) use is associated with lower rates of cardiovascular events in patients with stable coronary artery disease (CAD) but without heart failure (HF) receiving contemporary medical management. Using data from the Reduction of Atherothrombosis for Continued Health (REACH) registry, we examined, using propensity score approaches, relationships between cardiovascular outcomes and ACEI/ARB use (64.1% users) in 20 909 outpatients with stable CAD and free of HF at baseline. As internal control, we assessed the relation between statin use and outcomes. At 4-year follow-up, the risk of cardiovascular death, MI, or stroke (primary outcome) was similar in ACEI/ARB users compared with non-users (hazard ratio, 1.03; 95% confidence interval [CI], 0.91-1.16; P = 0.66). Similarly, the risk of the primary outcome and cardiovascular hospitalization for atherothrombotic events (secondary outcome) was not reduced in ACEI/ARB users (hazard ratio, 1.08; 95% CI, 1.01-1.16; P = 0.04), nor were the rates of any of its components. Analyses using propensity score matching yielded similar results, as did sensitivity analyses accounting for missing covariates, changes in medications over time, or analysing separately ACEI and ARB use. In contrast, in the same cohort, statin use was associated with lower rates for all outcomes. Use of ACEI/ARB was not associated with better outcomes in stable CAD outpatients without HF. The benefit of ACEI/ARB seen in randomized clinical trials was not replicated in this large contemporary cohort, which questions their value in this specific subset.

An ACE in the Hole for Patients With Advanced Chronic Kidney Disease?

In the treatmentofpatientswithadvancedchronickidneydisease (CKD) (which can be considered present when the estimated glomerular filtration rate [GFR] falls to <20 mL/min/ 1.73m2 and individuals become eligible to accrue time on the kidney transplant waiting list in the United States), a paramount goal is preventing or retarding progression to endstage renal disease and the requirement of dialysis. At earlier stages of CKD, blockade of the renin-angiotensinaldosteronesystem(RAAS) is amainstay therapy; angiotensinconverting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) clearly slow renal function decline, especially among thosewith proteinuria. However, the use of ACEIs or ARBs in advanced CKD remains uncertain. This important clinical question is the subject of a new study by Hsu and colleagues.1 Physiciansmayhesitate to prescribeACEIs or ARBs in advanced CKD for several reasons. Angiotensin-converting enzymeinhibitorsandARBs increaseserumpotassiumlevels, and their use in advanced CKDmay lead to dangerous hyperkalemia. InitiationofRAASblockade isoftenassociatedwithshorttermreductions inGFR,asmuchas30%.This reduction is generally believed to be due to reductions in intraglomerular pressure, hemodynamically reversible and self-limited (unless there are unusual coexisting conditions, such as severe renal artery stenosis).2,3 However, in advancedCKD, a 30% difference in GFR may determine whether the patient needs immediate initiation of dialysis. There have also been reports of substantial increase in GFR (more than 30%) after cessation of ACEI or ARB therapy in advanced CKD, resulting in postponement of dialysis.4 Other investigatorshaveemphasized that theuseofACEIs andARBsheightens the riskof acute-on-chronic renal failure.5 PatientswithCKDareat increased risk for acutekidney injury,6 andnumerouspatientswithmoderateoradvancedCKDdonot recover fromanepisodeof dialysis-requiring acute kidney injury but instead become dependent on long-term dialysis. Therefore, a superimposed episodeof severe acute kidney injury can immediately precipitate end-stage renal disease in some CKD patients.7 Thus, although somedata from randomized clinical trials suggest that RAAS blockade can be implemented safely and is efficacious in advanced CKD,8,9 much uncertainty remains about use of ACEIs andARBs in non–clinical trial participants with advancedCKD,particularly the elderly. The studybyHsu andcolleagues1usesacomprehensiveTaiwanesedatabase that captures health care utilization data of more than 95% of the hospitals in Taiwan and99%of the country’s population of 23 million. The investigators studied 28497patientswith stable, hypertensive, advanced CKD receiving erythropoiesisstimulatingagent (ESA) therapywhohaveserumcreatinine levels greater than 6 mg/dL (to convert to micromoles per liter, multiplyby88.4).Of these, 14 117usedACEIs/ARBs, and14380 werenonusers.UseofACEIs/ARBswasassociatedwitha lower hazard ratio for long-term dialysis (0.94 [95% CI, 0.91-0.97]) andthecompositeoutcomeof long-termdialysisordeath (0.94 [0.92-0.97]). Similar results were seen in several sensitivity analyses. The strengths of this study include its large size and its being nationally representative. The large proportion of patients with diabetes mellitus enhances generalizability because these patientswere excluded fromprior studies.8,9Hsu and colleagues1 provide reassuring information complementing the data from randomized clinical trials that RAAS blockadecanbesafely implementedeven inadvancedCKD.8,9Based on the age and sex distribution provided (more than half the patientswere older than65years and female), all patients had an estimated GFR of 12 mL/min/1.73m2 or less. A large, randomized clinical trial seems unlikely to be undertaken in this subset of patients in the foreseeable future. However, several caveats must be kept in mind when interpreting these data. No information regarding blood pressure,proteinuria,orother importantpatient-level clinical characteristics was provided. Themajor weakness of this study is that the actual levels of renal function were unknown because the database did not contain serum creatinine values. Instead, the level of renal functionwas inferred based onprescription of an ESA. The authors’ claim that the 28 497 patients studied had serum creatinine levels of greater than 6 mg/dL (andhematocrit levels of <28%) is basedonTaiwanNational Health Insurance reimbursement regulations bywhich patients meeting these criteria “could receive ESA treatment tomaintainahematocrit levelnot exceeding36%.”1Thus, confoundingbydifferences in the level ofGFRbetweenusers and nonusers of ACEIs/ARBs is a concern. The strength of the association between the level of GFR and the need for dialysis is very strong,10 at anorder ofmagnitude stronger than the association between the level of GFR and other adverse outcomes, such as cardiovascular disease.11 Hence, if ACEI/ARB users had on average even slightly higher levels of GFR, confounding may account for the rather modest observed effect size (approximately 6%). BlockadeofRAAS is known to lower hematocrit levels in CKDpatients12; hence, use of anESAmay be triggered amongACEI/ARBusers at higher GFR levels than ACEI/ARB nonusers. In addition,patientswithadvancedCKDwhoaremoreadherent to treatment regimens may be more likely to be prescribedACEIs/ARBs because nephrologistsmay trust them to come reliably for follow-up appointments and toundergo freRelated article page 347 Renin-Angiotensin System Blockade in CKD Original Investigation Research

Drugs affecting the renin-angiotensin system and survival from cancer: a population based study of breast, colorectal and prostate cancer patient cohorts

BackgroundAngiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly prescribed to the growing number of cancer patients (more than two million in the UK alone) often to treat hypertension. However, increased fatal cancer in ARB users in a randomized trial and increased breast cancer recurrence rates in ACEI users in a recent observational study have raised concerns about their safety in cancer patients. We investigated whether ACEI or ARB use after breast, colorectal or prostate cancer diagnosis was associated with increased risk of cancer-specific mortality.MethodsPopulation-based cohorts of 9,814 breast, 4,762 colorectal and 6,339 prostate cancer patients newly diagnosed from 1998 to 2006 were identified in the UK Clinical Practice Research Datalink and confirmed by cancer registry linkage. Cancer-specific and all-cause mortality were identified from Office of National Statistics mortality data in 2011 (allowing up to 13 years of follow-up). A nested case–control analysis was conducted to compare ACEI/ARB use (from general practitioner prescription records) in cancer patients dying from cancer with up to five controls (not dying from cancer). Conditional logistic regression estimated the risk of cancer-specific, and all-cause, death in ACEI/ARB users compared with non-users.ResultsThe main analysis included 1,435 breast, 1,511 colorectal and 1,184 prostate cancer-specific deaths (and 7,106 breast, 7,291 colorectal and 5,849 prostate cancer controls). There was no increase in cancer-specific mortality in patients using ARBs after diagnosis of breast (adjusted odds ratio (OR) = 1.06 95% confidence interval (CI) 0.84, 1.35), colorectal (adjusted OR = 0.82 95% CI 0.64, 1.07) or prostate cancer (adjusted OR = 0.79 95% CI 0.61, 1.03). There was also no evidence of increases in cancer-specific mortality with ACEI use for breast (adjusted OR = 1.06 95% CI 0.89, 1.27), colorectal (adjusted OR = 0.78 95% CI 0.66, 0.92) or prostate cancer (adjusted OR = 0.78 95% CI 0.66, 0.92).ConclusionsOverall, we found no evidence of increased risks of cancer-specific mortality in breast, colorectal or prostate cancer patients who used ACEI or ARBs after diagnosis. These results provide some reassurance that these medications are safe in patients diagnosed with these cancers.

Angiotensin II receptor antagonists in acute coronary syndromes

It is well known that inappropriate or exaggerated activity of the renin-angiotensin system might contribute to the development of systemic hypertension with consequent organ injury and associated increased risk of acute cardiovascular (CV) diseases. This review will discuss evidence form basic research and clinical studies, investigating the efficacy of angiotensin II receptor blockers (ARBs) in the management of acute coronary syndromes (ACS). This narrative review is based on the material found on MEDLINE and PubMed up to June 2013. We looked for the terms 'angiotensin, AT1 receptor, ACE inhibitors' in combination with 'acute coronary syndromes, acute myocardial infarction, pathophysiology'. Preclinical studies showed relevant protective effects of ARBs to reduce adverse cardiac remodelling in animal models of acute cardiac ischaemia. However, although recommended in Consensus guidelines as a good alternative to angiotensin-converting enzyme inhibitors (ACEIs), clinical studies did not confirm a superior efficacy of the ARBs as compared to ACEIs. As a matter of fact for some authors, these drugs might potentially have deleterious effects increasing the CV risk. Emerging evidence from clinical trials suggests that the use of ARBs in ACS might be controversial, and caution should be used for their clinical use to replace ACEIs in ACS.

Abstract 18279: Contemporary Trends of Optimal Evidence-Based Medical Therapy at Discharge for Patients Surviving Acute Myocardial Infarction From Korea Acute Myocardial Infarction Registry

Background: Most published studies about the contemporary trends in optimal medical therapy (OMT) were conducted more than 5 years ago. Furthermore, In Asia, only limited data are available for the recent trend of OMT at discharge after acute myocardial infarction (AMI). The aims of this study is (1) to describe the contemporary, as well as changing, prescribing of 4 effective cardiac medications in post-MI hospital survivors and (2) to determine whether use of 4 effective cardiac medications at the time of hospital discharge differ on the basis of age or gender. Methods: The Korea AMI Registry (November 2005-June 2011) were multicenter observational study. We examined the discharge medications among 22,646 post-MI survivors who did not have any documented contraindications to anti-platelet drugs, beta-blockers (BBs), angiotensin converting enzyme inhibitors (ACE-I)/ angiotensin II receptor blockers (ARBs) or statins in 6 periods by 12-month interval. OMT was defined as the use of all 4 indicated medications. Results: Particularly marked relative increase from period 1 to period 6 were observed in the use of BBs (from 70.3% to 84.5%) and statins (from 77.4% to 83.2%), whereas less dramatic increases were noted in the use of ACE-I/ARBs. Among ACE-Is/ARBs users, marked increases in the use of ARBs (from 17.4% to 32.2%) and declines in the use of ACE-Is (65.7% to 49.3%) were observed over time. Consistent with these trends, there were also marked increases in the use of OMT (from 48.9% to 62.3%). The odds ratios of the use of OMT from period 1 to period 6 were as follows: 1, 1.11 (p=0.034), 1.18 (p=0.001), 1.32 (p &lt;0.001), 1.41 (p &lt;0.001), and 1.57 (p &lt;0.001), respectively, in overall. The use of OMT was significantly higher in men than women over time (p &lt;0.05). Among patients aged 65 years or less, the use of OMT was significantly higher in men than women, whereas there was no significant difference between men and women over time among patients aged 65 to 75 years. Among patients aged more than 75 years, the use of OMT was significantly higher in women than men over time. Conclusions: National health improvement program implemented from 2007 markedly increased the use of all 4 effective cardiac medications, particularly in elderly women who were no more undertreated in our study.

Characteristics, management, and outcomes for patients during hospitalization due to worsening heart failure—A report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)

BackgroundThe characteristics, in-hospital management, and outcomes of patients hospitalized with worsening heart failure (HF) have been described by large-scale registries performed mainly in the USA and Europe. However, little information is available in Japan. We thus clarified the characteristics and clinical status as well as in-hospital management and outcomes among patients hospitalized with worsening HF in Japan and compared them with those reported in previous studies. MethodsThe Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in patients hospitalized with worsening HF. From the total cohort of JCARE-CARD, 1677 patients were randomly selected and their detailed data during acute phase were collected as another registry database in the present study. The characteristics, in-hospital management, and outcomes were analyzed. ResultsThe mean age was 70.7 years and 59.4% were male. Etiology was ischemic in 34.0% and mean left ventricular ejection fraction was 42.5%. Carperitide was highly used as in-hospital management in Japan (33.5%) compared to the use of nesiritide in the USA (8–11%). The use of angiotensin-converting enzyme inhibitors was lower and angiotensin II receptor blockers (ARB) were more commonly used in this study compared to other studies in the USA and Europe. In-hospital crude mortality rate was comparable among studies (4–8%), however, length of stay was longer in Japan (15–20 versus 4–9 days). ConclusionsThe characteristics, clinical status, and laboratory data on admission in patients hospitalized with worsening HF were similar between the present study and previous Japanese and western studies. Management was also similar except for higher use of carperitide and ARB. The most striking difference between Japanese registries and those from the USA and Europe was the longer length of stay.

Prevalence and clinical characteristics of primary aldosteronism in Japanese patients with type 2 diabetes mellitus and hypertension

The prevalence of primary aldosteronism (PA) is around 3-15% in patients with hypertension. Hypertension is a frequent complication of type 2 diabetes mellitus (DM) because of the close etiological relationship between these two diseases. However, the possibility of PA in patients with DM and hypertension is often overlooked and the prevalence of PA in patients with DM and hypertension in Japan is unknown. We enrolled 124 hospitalized patients with both DM and hypertension. PA was diagnosed according to the modified criteria for Japanese patients. We examined the prevalence of PA and compared clinical characteristics between patients with and without PA. In another analysis of 43 patients with a confirmed diagnosis of PA, we compared the characteristics of patients with and without DM. Overall, 14/124 patients with DM and hypertension (11.3%) were diagnosed with PA. Multivariate logistic regression showed that the duration of DM was significantly shorter in the PA group. Fisher's direct probability test revealed that history of hypertension before the diagnosis of DM was a significant factor in patients with PA. Treatment with an angiotensin II receptor blocker (ARB) did not affect the diagnosis of PA in these patients. Among 43 patients with PA, those with DM were significantly older and the delay to the diagnosis of PA was significantly longer compared with patients without DM. In conclusion, almost 10% of patients with DM and hypertension actually have PA. More extensive screening for PA is recommended in patients with DM and hypertension, regardless of the use of ARBs.

Severe Hyponatremia Associated with the Use of Angiotensin II Receptor Blocker/thiazide Combinations

There are several widely used combinations of angiotensin II receptor blocker (ARB)/thiazide. The complimentary mechanism of action for such anti-hypertensive therapies is that, while ARB inhibits the vasoconstricting and aldosterone-secreting effects of angiotensin II, hydrochlorothiazide affects the renal tubular mechanisms of electrolyte reabsorption and increases excretion of sodium and chloride in the distal tubule, consequently promoting water excretion. In addition, hypokalemia, which may be triggered by a hydrochlorothiazide-induced increase in urinary potassium loss, is resisted by the use of ARB. Hence, the ARB/thiazide combination is safe in terms of potassium imbalance. For these reasons, fixed-dose ARB/thiazide combination anti-hypertensive drugs have been widely used for the treatment of hypertension. However, there have not been many studies done regarding cases where patients under such regimens showed severe hyponatremia, even when the amount of thiazide included was low. Here we report two cases in which severe hyponatremia occurred following treatment with the ARB/thiazide combinations. Upon discontinuation of the regimen, both patients showed recovery from hyponatremia.

Pneumonia Risk and Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

BackgroundRecent studies have shown that use of angiotensin-converting enzyme (ACE) inhibitors may decrease pneumonia risk in various populations. We investigated the effect of ACE inhibitors and angiotensin II receptor blockers (ARBs) on pneumonia hospitalization in the general population of Taiwan.MethodsWe conducted a case-crossover study using the Taiwan Longitudinal Health Insurance Database for the year 2005. Data from patients hospitalized for the first time for pneumonia during 1997–2007 were analyzed. The case period was defined as the 30 days before admission; the periods 90 to 120 days and 180 to 210 days before admission were used as control periods. Prescribing status of ACE inhibitors and ARBs during the 3 periods was assessed for each patient. Conditional logistic regression was used to estimate the odds ratio (OR) for pneumonia associated with use of ACE inhibitors and ARBs.ResultsWe identified 10 990 cases of hospitalization for new pneumonia. After adjustment for time-variant confounding factors, pneumonia was not associated with use of ACEI or ARBS: the ORs were 0.99 (95% CI, 0.81–1.21) and 0.96 (0.72–1.28), respectively. No association was seen for cumulative defined daily doses (DDDs), as compared with nonusers, for 0 to 30, 31 to 60, or more than 60 DDDs. The results were found to be robust in sensitivity analysis.ConclusionsNeither the use nor cumulative dose of ACE inhibitors or ARBs was associated with pneumonia among the Taiwanese general population.

Heart Failure Therapy

HEART FAILURE WITH PRESERVED EJECTION FRACtion is a syndrome of volume overload and exertional intolerance marked by myocardial stiffness. Sophisticated investigations have also delineated multiple other pathophysiologic mechanisms, including vascular and renal dysfunction, chronotropic incompetence, energetic and metabolic derangements, and contractile abnormalities. However, other than the clinical similarities with heart failure with reduced ejection fraction, there is little evidence to support the notion that the 2 conditions are related pathophysiologically. Moreover, these disorders appear to be distinct and not part of a continuum of disease. Although basic science, observational studies, and clinical trials support heart failure with reduced ejection fraction as a condition of neurohormonal activation, the same is not true for heart failure with preserved ejection fraction. In fact, renin-angiotensin system antagonism with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in heart failure with preserved ejection fraction has not been effective—although not harmful—in randomized trials to date. Yet, these trials have significant limitations, including issues of power, selection bias, and crossovers. In this issue of JAMA, Lund and colleagues use a large, well-characterized registry to further explore the use of ACE inhibitors and ARBs in heart failure with preserved ejection fraction. Using the Swedish Heart Failure registry of 41 791 patients (n=16 216 with heart failure with preserved ejection fraction), the authors report that use of renin-angiotensin system antagonists in heart failure with preserved ejection fraction was associated with a statistically significant reduction in mortality (HR, 0.91; 95% CI, 0.85-0.98, P= .008) after the necessary adjustments for confounding factors, such as differences in baseline characteristics between those treated and not treated with renin-angiotensin system antagonists. The authors also use clinical trial techniques, eg, calculation of sample size to strengthen their analysis. Strengths of the study include the size of the cohort, the completeness and rigor of data collection, and careful propensity matching. In addition, the investigators provide consistency analyses that demonstrated both a dose-response association and confirmation of renin-angiotensin system antagonist benefit in a population with heart failure with reduced ejection fraction who were drawn from the same registry. Importantly, the authors also note that, in contrast to randomized trials involving patients with heart failure with preserved ejection fraction, the patients in their registry more accurately reflect those treated in routine clinical practice. However, there are important limitations that should be considered in the interpretation of the study by Lund et al. For example, the heart failure with preserved ejection fraction population studied was defined by a left ventricular ejection fraction (LVEF) of 40%, which represents significant systolic dysfunction. Despite the lack of an interaction between LVEF and the mortality benefit of renin-angiotensin system inhibition, the authors note that the nominal benefits were attenuated among patients with LVEF of more than 50%. Furthermore, heart failure was defined clinically by a large number of practitioners who had variable specialty training, thereby calling into question who was being treated. Also, it is not known whether renin-angiotensin system antagonists were specifically prescribed for the treatment of heart failure per se or for another condition, such as hypertension. In fact, there was a significant interaction P value noted for blood pressure in the analysis. A concomitant analysis using a different class of antihypertensive agents would have been of interest. At the heart of the matter is whether any set of sophisticated statistical techniques can ever fully account for confounding in an observational study. Variability among health care practitioners, time-dependent changes in health status and medical therapy, and differences in socioeconomic status are all important sources of confounding that are not fully accounted for by measured covariates and not only influence the decision to use specific drugs but are known to independently be related to outcomes. In fact, as further statistical adjustments are made to the findings, the magnitude of the benefit declines. The limitations that the au-

Association of Angiotensin-Converting Enzyme Inhibitor Therapy Initiation With a Reduction in Hemoglobin Levels in Patients Without Renal Failure

ObjectiveTo investigate whether treatment initiated with an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB) for patients with ischemic heart disease, hypertension, or diabetes causes a reduction in hemoglobin (Hb) levels. Patients and MethodsThis was a retrospective cohort analysis using the computerized database of a large health maintenance organization. Included were all adults with a first purchase of an ACE-I, an ARB, or a calcium channel blocker (CCB) between January 1, 2004, and December 31, 2009, defined as the index date. Measures of Hb levels before and 1 year after the index date were reviewed, and the change was calculated. All the analyses were stratified by pharmaceutical class. The main exposure variables were the proportion of days covered (PDC) by these drugs and the mean enalapril dosage (for enalapril users only). ResultsLevels of Hb before and after treatment were available for 14,754 patients taking ACE-Is, 751 taking ARBs, and 3087 taking CCBs. A high PDC was significantly associated with greater yearly reductions in Hb levels compared with a low PDC for CCB use, but was more pronounced for ACE-I and ARB use. A high PDC was also associated with a higher odds of developing anemia in ACE-I users (odds ratio [OR], 1.59; P<.001) and ARB users (OR, 2.21; P=.05). In nonanemic enalapril users, every 10-mg increment in daily dose was associated with an OR of 1.45 for the development of anemia (P<.001). The association remained after excluding nonadherent patients. ConclusionLevels of Hb are reduced during the first year of use of ACE-Is and to a lesser extent with use of ARBs. This association is dose dependent and is not explained by patient adherence.

Abstract 124: The Effectiveness of Angiotensin Converting Enzyme Inhibitors, Angiotensin II Receptor blocker, or Combination in Reducing Left Ventricular Hypertrophy in Hypertensive Patients: A Systematic Review

Background: Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are well established antihypertensive medications. Their role in reducing left ventricular hypertrophy (LVH) over other antihypertensives has also been clearly delineated on previous trials and meta-analysis. However, the difference in LVH reduction between ACEIs, ARBs or their combination is still unknown. Data Sources: The Cochrane Control Trials Register, PUBMED (1970 to April 2012), and hand selected reference list of English-language trials. Study Selection: Fourteen clinical trials comparing ACEI, ARB or both with outcome of interest in hypertensive patients, with duration of at least 6 months and that had minimum 20 patients were found. Data extraction: A predefined data extraction protocol was establish that included study reference, objective, design, population demographics, various interventions, outcomes and study quality. Results: Eleven randomized double blinded trials, 2 randomized open label trials and one case control trials were identified. Nine compared ACEI to ARB only and the remaining 5 compared ACEI, ARB with ACEI and ARB. There is high evidence that the use of ACEI or ARB in hypertensive patient with LVH for duration of at least 6 months, results in significant reduction in left ventricular hypertrophy measured by echocardiography or MRI as left ventricular mass (LVM) and or left ventricular mass index (LVMI). There is no significant difference between the use of ACEI or ARB in LVH reduction. When comparing combination therapy of ACEI and ARB to monotherapy of either ACEI or ARB, there is some evidence of further regression in LVH with combination therapy. The difference was more pronounced in diabetics. Limitations: Studies had small sample sizes with varied duration of therapy in diverse clinical settings, using different ACEIs and ARBs. Conclusion: The current evidence shows that the use of ACEI or ARB in hypertensive patients with LVH results in reduction in LVH. There is no significant difference in LVH reduction between use of ACEI or ARB. The use of both ACEI and ARB provides additional reduction in LVH especially in diabetics; there is however need for larger studies to better delineate these differences.

Population-based study of statins, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors on pneumonia-related outcomes.

Studies suggest that statins and angiotensin-converting enzyme (ACE) inhibitors might be beneficial for the treatment of infections. Our purpose was to examine the association of statin, ACE inhibitor, and angiotensin II receptor blocker (ARB) use with pneumonia-related outcomes. We conducted a retrospective cohort study using Department of Veterans Affairs data of patients aged ≥ 65 years hospitalized with pneumonia. We performed propensity-score matching for 3 medication classes simultaneously. Of 50119 potentially eligible patients, we matched 11498 cases with 11498 controls. Mortality at 30 days was 13%; 34% used statins, 30% ACE inhibitors, and 4% ARBs. In adjusted models, prior statin use was associated with decreased mortality (odds ratio [OR], 0.74; 95% confidence interval [CI], .68-.82) and mechanical ventilation (OR, 0.81; 95% CI, .70-.94), and inpatient use with decreased mortality (OR, 0.68; 95% CI, .59-.78) and mechanical ventilation (OR, 0.68; 95% CI, .60-.90). Prior (OR, 0.88; 95% CI, .80-.97) and inpatient (OR, 0.58; 95% CI, .48-.69) ACE inhibitor use was associated with decreased mortality. Prior (OR, 0.73; 95% CI, .58-.92) and inpatient ARB use (OR, 0.47; 95% CI, .30-.72) was only associated with decreased mortality. Use of all 3 medications was associated with reduced length of stay. Statins, and to a lesser extent ACE inhibitors and ARBs, are associated with improved pneumonia-related outcomes. Prospective cohort and randomized controlled trials are needed to examine potential mechanisms of action and whether acute initiation at the time of presentation with these infections is beneficial.

Comparison of medium-dose losartan/hydrochlorothiazide and maximal-dose angiotensin II receptor blockers in the treatment of Japanese patients with uncontrolled hypertension: the Kobe-CONNECT Study

The objective of this study is to examine the effects of thiazide diuretics, plus medium-dose losartan versus maximal-dose angiotensin II receptor blockers (ARBs) on blood pressure (BP) in Japanese patients with uncontrolled hypertension despite the use of medium-dose ARBs. Hypertensive patients in whom BP was inadequately controlled by treatment with medium-dose ARBs alone or with calcium-channel blockers were enrolled. Patients were randomly assigned to a fixed-dose combination of 50 mg per day losartan and 12.5 mg per day hydrochlorothiazide (HCTZ; n=98), or to a maximal dose of current ARBs (n=95). The reduction in office BP from baseline was significantly larger in the losartan/HCTZ group than in the maximal-dose ARB group (systolic BP -22.7±13.7 vs. -11.7±13.0 mm Hg, diastolic BP -9.6±10.9 vs. -4.5±11.0 mm Hg; P<0.01, respectively). The proportion of patients in whom the therapeutic target BP was achieved was greater in the losartan/HCTZ group than in the maximal-dose ARB group (59.2 vs. 26.3%; P<0.001). Both early-morning and evening BP were controlled more effectively over 1 year of treatment in the losartan/HCTZ group than in the maximal-dose ARB group (the mean BP difference between the groups, early-morning: 5.6 mm Hg (P=0.001), evening: 3.8 mm Hg (P=0.049)). Adverse changes in serum potassium and uric acid were observed in the losartan/HCTZ group; however, both changes were very slight, and the values were still within the normal range. The concomitant usage of losartan and HCTZ had no influence on glucose metabolism and lipid profiles. Declines in plasma N-terminal pro-brain natriuretic peptide levels and urinary albumin excretion were observed in the losartan/HCTZ group, but not in the maximal-dose ARB group. Switching from medium-dose ARBs to losartan plus HCTZ reduced both office and home BP efficiently in patients with uncontrolled hypertension.

Angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers and the risk of developing rheumatoid arthritis in antihypertensive drug users

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective in the treatment of cardiovascular disease. Next to effects on hypertension and cardiac function, these drugs have anti-inflammatory and immunomodulating properties which may either facilitate or protect against the development of autoimmunity, potentially resulting in autoimmune diseases. Therefore, we determined in the current study the association between ACE inhibitor and ARB use and incident rheumatoid arthritis (RA). A matched case-control study was conducted among patients treated with antihypertensive drugs using the Netherlands Information Network of General Practice (LINH) database in 2001-2006. Cases were patients with a first-time diagnosis of RA. Each case was matched to five controls for age, sex, and index date, which was selected 1 year before the first diagnosis of RA. ACE inhibitor and ARB exposure was considered to be any prescription issued in the period before index date. Logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CI). Our study included 211 cases and 667 matched controls. After controlling for potential confounders, ever use of ACE inhibitors or ARBs was not associated with incident RA (adjusted ORs [95%CI], 0.99 [0.55-1.79] and 1.02 [0.67-1.56], respectively). The adjusted ORs (95%CI) for current and past use of ACE inhibitors were 1.18 (0.75-1.85) and 0.61 (0.28-1.35). For current and past use of ARBs, these adjusted ORs (95%CI) were 1.40 (0.80-2.45) and 0.29 (0.05-1.67), respectively. No duration and dose-effect relationship was observed. ACE inhibitor or ARB use is not associated with incident RA.