Evidence of reduced cardiovascular morbidity and mortality as well as cost support thiazide diuretics as the first-line choice for treatment of hypertension. The purpose of this study was to determine the proportion of senior hypertensives that received thiazide diuretics as first-line treatment, and to determine if cardiovascular and other potentially relevant comorbidities predict the choice of first-line therapy.British Columbia PharmaCare data were used to determine the cohort of seniors (residents aged 65 or older) who received their first reimbursed hypertension drug during the period 1993 to 2000. These individual records were linked to medical and hospital claims data using the British Columbia Linked Health Database to find the subset that had diagnoses indicating the presence of hypertension as well as cardiovascular and other relevant comorbidities. Rates of first-line thiazide prescribing as proportion of all first-line treatment were analysed, accounting for patient age, sex, overall clinical complexity, and potentially relevant comorbidities. For the period 1993 to 2000, 82,824 seniors who had diagnoses of hypertension were identified as new users of hypertension drugs. The overall rate at which thiazides were used as first-line treatment varied from 38% among senior hypertensives without any potentially relevant comorbidity to 9% among hypertensives with previous acute myocardial infarction. The rate of first-line thiazide diuretic prescribing for patients with and without potentially relevant comorbidities increased over the study period. Women were more likely than men, and older patients were more likely than younger, to receive first-line thiazide therapy.Findings indicate that first-line prescribing practices for hypertension are not consistent with the evidence from randomized control trials measuring morbidity and mortality. The health and financial cost of not selecting the most effective and least costly therapeutic options are significant. Prescription practices for hypertension were not consistent with existing evidence--newer and more expensive drugs were prescribed preferentially despite evidence that thiazides are equally or more effective Hypertension significantly increases the risk of serious cardiovascular morbidity and mortality and is the leading primary diagnosis for patient visits to physicians' offices in Canada . PharmacThe purpose of this study was to determine whether prescribing practices are in accordance with this evidence. Using population-based research datasets at the University of British Columbia's Centre for Health Services and Policy Research, we calculated trends in first-line prescribing of antihypertensive drugs for seniors (residents aged 65 or older) in the province of British Columbia over the period of 1993 to 2000. We analyse the likelihood of first-line thiazide prescribing as a function of patient age, sex, overall clinical complexity, and potentially relevant comorbidities.Administrative data from public medical, hospital, and pharmaceutical insurance programs were analyzed to determine trends in first-line hypertension drug use. All residents of British Columbia are covered under a comprehensive public health insurance plan for medical and hospital services. Public insurance for prescription drugs is restricted to selected populations, but includes universal and comprehensive drug coverage for all seniors . AdminisThe study cohort included all community-dwelling seniors who had evidence of first-time hypertension drug use and hypertension diagnosed in administrative databases. The classes of hypertension drugs were defined by the World Health Organization Anatomical Therapeutic Chemical classification system, and included angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers, beta-blockers, calcium-channel blockers, alpha-antagonists, thiazide diuretics, nonthiazide diuretics, and other antihypertensives . First-time hypertension drug use was defined as the receipt of any hypertension drug following at least one year of eligibility for PharmaCare coverage during which no prescriptions for any hypertension drugs were filled. Eligibility for coverage was measured starting in January 1992. A patient was considered a first-time user only once; those who stopped drug treatment and then filled prescriptions for antihypertensive drugs a year or more later were only included in the analysis of first-line use based on their initial course of treatment.The study cohort was limited to the subset of first-time users of antihypertensive drugs who had a diagnosis of hypertension in administrative data records. This included patients for whom there was at least one diagnosis of hypertension  in Medical Services Plan and Hospital Separations databases spanning two years prior to the date of first-line hypertension treatment and one year following first-line treatment. Each Medical Services Plan record pertains to a fee-for-service billing and contains one diagnosis for the physician visit or related service. This is assumed the primary diagnosis for the visit or service. Hospital Separations records describe patient stays at the point of discharge and contain up to 16 diagnoses, all of which were searched. In order to avoid bias as a result of under-reporting the diagnosis of hypertension, diagnoses of hypertension were sought from records spanning two years prior to and one year following the first prescription for hypertension. Diagnoses occurring after drug use were included in the study because, for approximately one-third of users of hypertension drugs, the diagnosis of hypertension was recorded as the primary diagnosis during follow-up after the initiation of drug treatment.Medical and hospital data spanning two years prior to the date of first-time hypertension treatment were searched for International Classification of Diseases-9 diagnostic codes pertaining to potentially relevant comorbidities. Identified using “Expanded Diagnostic Clusters” , the diaPatients' first-line therapy was determined by the categories of drugs that they received on the date they first filled a hypertension prescription. In addition to patients who started treatment with the purchase of a thiazide alone or a combination product that contained thiazides, patients whose first hypertension treatment was a thiazide diuretic along with another antihypertensive drug were also considered to be receiving first-line thiazide therapy.The analysis is based on data describing the entire population of users fitting the protocol definitions. Summary statistics describe average cost per day of treatment for each category of drug and first-line treatment choices over time. Multivariate logistic regression determined the probability that a patient would receive a thiazide diuretic as a first-line drug treatment. Independent variables for the multivariate analysis included patient age, sex, and year of first prescription. As a measure of overall clinical complexity, the regression included the number of different types of prescription drug purchased within the year prior to the patient's first antihypertensive drug purchase. Binary variables indicating prior diagnosis of comorbidities were included as independent variables. The analysis also included a binary variable that identified patients who filled no more antihypertensive prescriptions during the year following their first antihypertensive drug purchase. Wald chi-square tests were calculated to determine statistical significance.A total of 82,824 British Columbia residents over age 65 received an antihypertensive drug for their first time between 1993 and 2000. Over the period of study, the share of British Columbia seniors who were first-time users of antihypertensive drugs in a given year increased from 1.8% to 2.2%. The median age of patient at the date of first-time hypertension use was 72; 55% of newly treated seniors were female.The average cost per days-supply of hypertension treatment received by British Columbia seniors varied by type of drug prescribed and was affected by policies implemented over the period of study . AvailabThiazide diuretics were prescribed as a first-line therapy for less than a third (29%) of newly treated patients. Over time, the trend in the share of newly treated patients that received thiazide diuretics as a first-line therapy was similar for those with and without diagnoses indicating potentially influential comorbidities. p < 0.001), gender , and age . The measure of overall clinical complexity (number of different drugs used) did not have a significant impact. After adjusting for these factors, all potentially influential concurrent diagnoses other than migraine headache were associated with a statistically significant reduction in the likelihood of first-line thiazide diuretic use. Patients with diagnoses of acute MI, angina, or chronic renal failure were less than half as likely to receive thiazide diuretics as those without such diagnoses.The proportion of newly treated patients receiving thiazides as first-line therapy varied according to the presence of comorbidity diagnoses . Nearly Despite the advantage that it is population based, this research study is limited by the use of administrative claims data. Claims data may result in under-reporting of actual conditions ,13. In aThe overall share of British Columbia senior hypertensives that received thiazide diuretics as first-line treatment ranged from 21% to 34% between 1993 and 2000. Thiazide use was affected by the presence of diagnoses for certain comorbidities; however, the rates of first-line thiazide use were relatively low below 45%) for patients both with and without any evidence of conditions that might influence treatment choice. We believe that such rates of first-line thiazide use among newly treated hypertensive seniors are low, given the evidence for the morbidity and mortality benefit associated with the first-line use of this class of antihypertensive drugs % for pat,14 and tBecause the cost per day of treatment on alternative treatments is upwards of 100 times that of thiazide diuretics, the financial consequences of first-line treatment decisions are significant, even when limited to the group of “uncomplicated” cases. For the subset of patients with no comorbidities, the additional cost to British Columbia PharmaCare in 2000 stemming from decisions to treat newly hypertensive seniors with nonthiazides was approximately Can$1 million per year. This additional cost will accumulate for each year that these incident cases continue to receive treatment. It is therefore necessary for professional associations and those who pay for (and benefit from) pharmaceutical benefits to work together to ensure that prescribing practices more accurately reflect research evidence.One might conjecture that low rates of first-line thiazide use result from physicians' concerns regarding the presence of comorbidity. In our study, approximately half of the newly treated hypertensive seniors had diagnoses associated with specific comorbidities that may influence prescribers' beliefs about the appropriateness of thiazide diuretics. In all instances except migraine headaches, the presence of a comorbidity diagnosis predicted a decreased incidence of first-line thiazide use. Some of the associations are rational and consistent with outcomes evidence. Following acute MI, for example, beta-blockers and ACE-inhibitors are first-line choices because they have been shown in randomized controlled trials to reduce morbidity and mortality in addition to having a blood pressure lowering effect ,16. It iClinical practice guidelines starting in the early 1980s recognized the benefits of treatment with thiazide diuretics by recommending them as the first-line treatment of choice for virtually all hypertension patients ,23,24,25Given that hypertension treatment is one of the fastest growing drivers of seniors' drug expenditure in British Columbia , a critiThis analysis predates publication of the largest randomized antihypertensive trial designed to answer the question of which first-line antihypertensive is best, the ALLHAT trial . ALLHAT High blood pressure (hypertension) is common and increases the chances of developing heart disease. Different types of drugs are available for treating blood pressure, and they have been compared in many different studies. When doctors recommend a particular drug for a particular patient, they base their decision on the latest studies, on whether the patient has any other medical problems that might affect drug choice, and on the price differences between different drugs. If there are two drugs that have been shown to work equally well for a particular patient, the doctor should prescribe the cheaper one.The researchers wanted to see whether doctors follow the latest guidelines when they prescribe drugs for treating high blood pressure (antihypertensive drugs).They looked at which drugs doctors had given to people aged over 65 years with high blood pressure in British Columbia, Canada, from 1993 to 2000. They only looked at prescriptions for people who had never taken blood-pressure medication before, a total of 82,824 patients. The drug of choice for most of these patients is a thiazide. Thiazides belong to a class of drugs called diuretics, sometimes referred to as water pills. These drugs have been around for a long time and in most patients they are at least as effective as and much cheaper than any of the newer drugs.The prescription of thiazides in these patients increased from 22% to 33% during the study period, but it was consistently lower than it should have been based on the existing evidence.Doctors in British Columbia do not prescribe thiazides for seniors with high blood pressure as much as they should. As a consequence, some patients don't get the best treatment and the costs are considerably higher than they need to be. The reasons are not clear, but the findings suggest that doctors might not be up-to-date with the latest study results and guidelines. There have been more studies since 2002 and more efforts to educate doctors, and it would be interesting to know whether the current prescription practices better match the latest results.http://www.nhlbi.nih.gov) has information about antihypertensive drugs and their characteristics, including facts on a recent big study  that compared antihypertensive drugs: http://www.nhlbi.nih.gov/health/allhat/facts.htmThe website of the US National Heart, Lung, and Blood Institute (http://www.bpassoc.org.uk/information/information.htmInformation pages from the Blood Pressure Association, a UK-based charity: http://www.nlm.nih.gov/medlineplus/highbloodpressure.htmlMedline Plus information pages on blood pressure:


Morbidity in COPD results from a combination of factors including hypoxia-induced pulmonary hypertension, in part due to pulmonary vascular remodelling. Animal studies suggest a role of angiotensin II and acute studies in man concur. Whether chronic angiotensin-II blockade is beneficial is unknown. We studied the effects of an angiotensin-II antagonist losartan, on haemodynamic variables, exercise capacity and symptoms.This was a double-blind, randomized, parallel group, placebo- controlled study of 48 weeks duration. Forty patients with COPD and pulmonary hypertension (Tran tricuspid pressure gradient (TTPG) = 30 mmHg) were randomised to losartan 50 mg or placebo. Changes in TTPG were assessed at 3, 6 and 12 months.There was a trend for TTPG to increase in the placebo group (baseline 43.4 versus 48.4 mmHg at endpoint) and stay constant in the losartan group (baseline 42.8 versus 43.6 mmHg). More patients in the losartan group (50%) than in the placebo group (22%) showed a clinically meaningful reduction in TTPG at any timepoint; these effects seemed more marked in patients with higher baseline TTPG. There were no clear improvements in exercise capacity or symptoms.In this 12-month pilot study, losartan 50 mg had no statistically significant beneficial effect on TTPG, exercise capacity or symptoms in pulmonary hypertension secondary to obstructive disease. A sub-group of patients with higher TTPG may benefit. Pulmonary hypertension is the main cardiovascular complication of chronic obstructive pulmonary disease (COPD) and is associated with a substantial increase in morbidity and mortality -3. The mAlveolar hypoxia undoubtedly contributes to pulmonary hypertension in COPD and there is a correlation, albeit poor, between the pulmonary artery pressure and the degree of arterial hypoxaemia ,7. Struc1 receptor, is currently used for reducing central pressures in patients with heart failure [A possible therapeutic role for losartan, a selective angiotensin-II antagonist, in hypoxic pulmonary hypertension has been suggested by results from animal models  and acut failure  and is e failure  and left failure  and to r failure  in hyperWe hypothesized that long-term administration of losartan may benefit patients with pulmonary hypertension secondary to COPD, using echo-Doppler derived measurements of Tran tricuspid pressure gradient (TTPG) as an index of pulmonary hypertension. We, therefore, undertook a study to evaluate the effects of losartan on TTPG, exercise capacity, quality of life, arterial blood gases and safety in patients with cor pulmonale secondary to severe COPD.1/FVC ratio ≤ 70%), echocardiographic evidence of pulmonary arterial hypertension (TTPG ≥ 30 mmHg) and sitting systolic blood pressure ≥ 100 mmHg. Exclusion criteria included left ventricular dysfunction (ejection fraction <35%), myocardial infarction, significant renal impairment, recent infective exacerbation of COPD, or concomitant use of vasodilators, β-blockers or potassium-sparing diuretics. Patients were permitted to continue on their regular COPD therapy.Male or female patients, aged 50–80 years, were included. Patients had a clinical history of COPD, evidence of obstructive spirometry  to receive either losartan  or placebo for 48 weeks. Losartan 25 mg or a placebo tablet was administered once daily for 1 week. The dose was then increased to 50 mg daily , providing the patient's systolic blood pressure remained ≥ 100 mmHg. The dose could be down titrated once (to 25 mg) if necessary.The study protocol was approved by the hospital's research ethics committee, and all patients provided written informed consent to study participation.At the initial visit (week -4) patients underwent physical examination, spirometry, a practice exercise test (see below), echocardiography and safety blood/urine tests. For all eligible patients, tests were repeated at the baseline visit (week 0) when arterial blood gases were also measured.-1 and used to calculate the TTPG in mmHg, as previously described [Patients returned to the clinic at weeks 1, 4, 12, 24, 36 and 48 when blood pressure measurements and safety tests were repeated. Spirometry, echocardiography and exercise testing using a symptom-limited 10 m shuttle walk test  were repescribed . PulmonaA quality of life questionnaire   and PatiThe primary endpoint was change from baseline (week 0) in TTPG. Pre-specified secondary endpoints included change from baseline in other echocardiographic parameters including right ventricular systolic pressure, peak tricuspid regurgitant velocity, left ventricular fractional shortening and right ventricular wall thickness.Change from baseline in exercise capacity, breathlessness score after exercise ; and quality of life assessments were specified as secondary outcomes.This pilot study was designed with a sample size of 44 patients, to give a power of 85% to detect a 25% reduction in TTPG, assuming a baseline TTPG of 46 mmHg increasing by 3 mmHg in the placebo group during the year of the study and a standard deviation of 16 mmHg. This power calculation was based on studies of pulmonary arterial pressure estimated from measurement of TTPG in patients of a similar type , and the1 was 0.83 L (range 0.28–1.95 L), with the mean percent of predicted FEV1 being 35.3%. The mean FEV1/FVC ratio was 36% (range 14 to 69%) The distribution of patient characteristics, symptoms and clinical data at baseline  mmHg and at baseline was 43.1 9.2) mmHg. Based on all available data over the course of the study, the TTPG tended to increase in the placebo group and stay constant in the losartan group with mean increases of 5.03 mmHg and 0.84 mmHg, respectively,  than in the placebo group, 4/18 (22%), (p = 0.09).There were no significant differences between the treatment groups in the changes from baseline in the following secondary efficacy endpoints: right atrial pressure, peak tricuspid regurgitant velocity, right ventricular pressure, left ventricular fractional shortening and right ventricular wall thickness Table .Exploratory analysis Figure  suggesteSymptom-limited exercise capacity tended to stay constant over the course of the study in losartan-treated patients (n = 15); there was a mean decrease from baseline to week 48 of 0.2 shuttles completed  to 6.8 (1.2) between baseline and week 48; in the placebo group there was a corresponding decrease from 6.7 (2.0) to 6.4 (2.1). The p-value for the point estimate of treatment difference was 0.42. Exploratory analysis in those patients with baseline TTPG >40 mmHg failed to suggest a differential effect on symptom score.The St George's Hospital Respiratory Questionnaire produces three component scores  and an overall score; improvement in quality of life is denoted by a reduction in score. There was a mean decrease of 3.61 in overall score for losartan-treated patients and a mean increase of 1.70 for placebo-treated patients  of the Patient Health Survey (SF-36).Thirty-five of the forty patients reported at least one adverse event during the study, 16 (80%) in the losartan group and 19 (95%) in the placebo group. One patient (in the losartan group) died from peritonitis due to diverticular disease. Adverse experiences determined by the investigator to be possibly, probably or definitely drug related, were reported for seven patients (35%) in the losartan group and ten patients (50%) in the placebo group. Treatment was discontinued because of a drug-related adverse event by four patients, one in the losartan group (nausea with rash and hypotension) and three in the placebo group .Blood pressure control was not a significant problem. One patient in the losartan group had asymptomatic hypotension (and discontinued treatment); two patients in the placebo group experienced orthostatic symptoms (one discontinued therapy – see above).2for losartan-treated patients was 9.1 (1.2) kPa at baseline and 8.1 (1.3) kPa at study end; the corresponding figures for placebo-treated patients were 8.9 (1.8) and 8.6(1.5) kPa, respectively. For PaCO2, mean values were 5.6 (0.8) and 5.8 (0.7) kPa for losartan- and 5.5 (0.7) and 5.5 (1.0) kPa for placebo-treated patients at baseline and study end, respectively.There were no adverse changes in arterial blood gases. Mean (sd) PaODespite the encouraging data in animal models of chronic hypoxic pulmonary hypertension ,28, therThe rationale behind this study was based on the findings that angiotensin converting enzyme and angiotensin II are both involved in the pulmonary vascular remodelling associated with hypoxic pulmonary hypertension ,29 AngioIt is well recognized that the increased pulmonary vascular resistance in COPD may be due to a combination of reduced cross-sectional area of the pulmonary vascular bed in emphysema, hyperinflation, and hypoxic pulmonary vascular remodelling. We would expect losartan to target only the latter. The relative contribution of these factors almost certainly differs between COPD patients, and there may be a sub-population of patients who stand to benefit more than others.A number of methodological issues need to be considered before rejecting a beneficial effect. Firstly, fewer patients than planned completed the study, largely due to adverse events unrelated to study medication and more related to the elderly nature of the group. This may have reduced our power. Nonetheless, our pre-study assumptions  were not far from those observed  We conclude therefore that a change of this magnitude is unlikely in the group as a whole. A much larger study would be needed to confidently detect or exclude a smaller effect. There does appear to be a greater proportionate effect on TTPF in patients with higher baseline values raising the possibility of further study in this group. Secondly, the choice of assessments requires consideration. Studies of agents shown to be beneficial such as Iloprost  and BoseFinally, whilst our study was ongoing, other losartan studies ,38 usingIn conclusion, this pilot study of the effect of losartan 50 mg on pulmonary hypertension secondary to COPD showed no significant sustained differences between control and treatment groups over the course of one year. There was a trend to early benefit in terms of a slowing of the rate of decline of TTPG and exercise capacity which may warrants further study, particularly in patients with more severe disease, and at higher doses.1 Angiotensin II type 1 receptorATCOPD Chronic Obstructive pulmonary disease1 Forced expiratory volume in 1 secondFEVFVC Forced Vital CapacityLV Left ventricleRAP Right atrial pressureRA Right atriumRV Right ventricleTTPG Transtricuspid pressure gradientTo convert KPa to mmHg, multiply by 7.5This study was funded by Merck Sharp & Dohme Ltd. At the time of the work, PR & RB were employees of Merck Sharp & Dohme and may own stock/stock options.NM, PR, RB were involved in the design of the study. NM, PP, MH, BHS were involved in the acquision of clinical data. NM & PR wrote the manuscript. All authors read and approved the final manuscript.


Ronald Ma and colleagues discuss the differential diagnosis and management of a patient who presented with recurrent episodes of chest discomfort, palpitations, and labile blood pressure. Baseline electrocardiogram (ECG) was unremarkable. An exercise tolerance test was negative. On the day of admission, the patient described retrosternal chest tightness lasting 10 minutes. This was associated with palpitations and nausea. His medications were felodipine, propranolol, alprazolam, and thyroxine. On admission, he was markedly hypertensive (BP 182/123 mmHg). On examination, the patient was afebrile. His BP was persistently elevated. His pulse rate was 80 bpm. Cardiovascular examination was otherwise unremarkable. He had no audible carotid or abdominal bruits. Neurological examination was unremarkable. Fundoscopy was normal. Bedside urine analysis was normal. Plasma electrolytes, renal function, liver function, and amylase were all normal. Fasting glucose was 6.3 mmol/l. Heart size was normal on chest X-ray. ECG showed sinus rhythm (90 bpm) and incomplete right bundle branch block. The patient was initially treated for suspected acute coronary syndrome and was started on an intravenous nitrate infusion. Shortly afterwards, his BP abruptly dropped to 97/62 mmHg and the nitrate infusion was discontinued. Repeat ECG with right-sided chest leads did not show any evidence of right ventricular infarct. Serial troponin T tests were negative. On further questioning, he described a 6-month history of episodic chest discomfort, palpitations, and sweating. He also described marked fluctuation in blood pressure with home readings around 80/40 mmHg and markedly elevated readings in clinic. During admission, frequent fluctuation in BP with a systolic BP (SBP) between 106–226 mmHg and a diastolic BP (DBP) between 62–114 mmHg was noted. This was accompanied by a resting tachycardia with frequent fluctuation of heart rate.A 53-year-old man was admitted to hospital in September 2005 with chest pain. He had a history of nasopharyngeal carcinoma in 1986, for which he was treated with fractionated radiotherapy . His blood pressure (BP) was 100/70 mmHg at the time of diagnosis. He was in remission following radical radiotherapy, but had partial hypopituitarism for which he required thyroxine replacement. Six months prior to admission, he complained of chest discomfort, was noted to be hypertensive in clinic with BP 156/93 mmHg and pulse rate of 107 bpm, and was started on atenolol. Renal function tests, electrolytes, fasting lipids, thyroid-stimulating hormone, and free TPhaeochromocytoma was suspected on the basis of the patient's presenting symptoms and labile blood pressure, but repeated collections for urinary catecholamines were normal during admission despite documented paroxysms during the collections. The patient denied use of any recreational drugs. Psychiatric assessment did not support a diagnosis of anxiety disorder or panic attacks. Twenty-four hour ambulatory BP monitoring revealed a mean asleep BP of 107/69 mmHg with mean heart rate 85 bpm but frequent surges of BP during waking daily activities, with mean daytime BP 139/94 mmHg and average awake heart rate of 95 bpm . In viewClonidine was prescribed to the patient, which led to improvement in his symptoms as well as his BP. A repeat 24-hour ambulatory BP monitor 4 weeks later showed a mean BP of 126/83 mmHg with only one surge of BP to 175/100 mmHg and only 30% of SBP readings and 33% of DBP >140/90 mmHg. The patient remained well in July 2006 on clonidine 0.1 mg TDS.The presence of paroxysmal hypertension should always alert health-care providers to the possibility of a catecholamine-secreting phaeochromocytoma. The diagnosis is supported by the demonstration of elevated plasma or urine catecholamines or metanephrines . HoweverArterial baroreceptors provide a tonic inhibitory influence on sympathetic tone , failureA diagnosis of baroreflex failure should be suspected in patients with excessive excursion of heart rate during normal daily activities, often with marked fluctuation in blood pressure. The diagnosis is supported by the finding of absent bradycardia in response to a pressor such as phenylephrine or absent tachycardia in response to a depressor such as nitroprusside. Baroreflex failure can often be distinguished from pure autonomic failure. The presentation of autonomic failure is typically dominated by orthostatic hypotension, and often associated with supine hypertension and postprandial hypotension. Labile hypertension and episodic tachycardia are not usually observed. The presentation of baroreflex failure, on the other hand, often resembles that of phaeochromocytoma, with labile hypertension and episodic tachycardia, whilst orthostatic hypotension is rarely seen . SubjectTreatment is aimed at reducing the frequency and magnitude of the life-threatening surges in blood pressure. In addition, a secondary goal of therapy is to attenuate symptomatic hypotensive episodes. Behavioural therapy with relaxation training can help by reducing sympathetic surges. Clonidine, a centrally and peripherally acting α-adrenoceptor agonist, can dampen sympathetic activation to limit the extent of pressor surges. Treatment with clonidine reduces the frequency of attacks and attenuates the blood pressure and heart rate changes during an attack . In patiTable S1(37 KB DOC)Click here for additional data file.Text S2(77 KB PPT)Click here for additional data file.Presence of paroxysmal hypertension may indicate an underlying condition causing secondary hypertension.Labile hypertension may be due to hyperthyroidism, renovascular hypertension, seizure disorder, migraine, alcohol withdrawal, carcinoid syndrome, panic disorder, baroreflex failure, or drugs such as cocaine, amphetamines, or clozapine.Baroreflex failure should be considered in the differential diagnosis of labile hypertension, especially in subjects with a history of neck injury or neck irradiation.Treatment of baroreflex failure is aimed at reducing blood pressure surges and avoiding hypotensive episodes.


An understanding of the needs and behaviors of asthma patients is important in developing an asthma-related healthcare policy. The primary goal of the present review was to assess patient perspectives on key issues in asthma and its management, as captured in patient surveys.Local, national, and multinational asthma surveys were reviewed to assess patient perspectives, and where possible healthcare provider (HCP) perspectives, on key issues, including diagnosis, treatment, control, quality of life, and other patient-centered outcomes. Twenty-four surveys, conducted or published between 1997 and 2003 in Europe and North America, were included in this review. Substantial differences among studies prevented a formal meta-analysis; instead, data were pooled to allow for general comparisons and qualitative analysis.The results indicate that patients' knowledge of the underlying causes of asthma and treatment options remains inadequate. Moreover, patients often tolerate poor symptom control, possess meager knowledge of correct drug usage, and display insufficient adherence to therapy. Many patients have a low expectation of receiving an appropriate therapy or of having a positive encounter with the HCP. Among HCPs, there is evidence of inadequate understanding of disease etiology and poor or unstructured communication with patients, resulting often in inaccurate assessment of disease severity. Moreover, patients often underreport their symptoms and severity, which in turn could lead to misclassification and undertreatment.Improving patient education about the importance of achieving optimal asthma control, along with improved communication between patients and HCPs, emphasizing treatment options and optimal treatment of inflammation, may lead to better outcomes and improved asthma management in daily practice. Asthma is a chronic, inflammatory condition of the airways characterized by airway hyperresponsiveness and episodic respiratory symptoms, such as breathlessness, wheezing, chest tightness, and coughing. The prevalence of asthma continues to increase in many countries: the current estimate of 300 million people with asthma worldwide is expected to increase by 33% to 400 million by 2025 ,2. In adInternational surveys have been valuable for understanding and managing asthma. The International Study of Asthma and Allergies in Childhood, the European Community Respiratory Health Survey, and other surveys have provided much needed information on the global patterns of asthma prevalence from childhood to adulthood, and have generated new hypotheses for further testing and validation ,7-10. AnA review of asthma patient surveys in Europe and North America, conducted or published between 1997 and 2003, was undertaken by a general multibased literature search using keywords that included 'asthma' and 'survey'; additional searches were performed on key authors' names. The following initial selection criteria were used: observational/experimental survey design, patient-reported outcomes, perceptions or data related to asthma management, and physician-reported aspects of asthma management. From a total of 68 surveys initially screened, 24 surveys  and analyses were ultimately selected to provide a balanced data pool across a broad range of issues -32. ThesData from all studies were extracted in a systematic fashion into a large two-dimensional matrix. This approach simplified identification of subsets of surveys in which the methods, including design, populations, and outcomes, were sufficiently similar for possible pooled analysis. The following main criteria were used to structure the matrix: the period of data collection, the nature of data extraction (interview/self-reported questionnaire), questionnaire type (standardized/nonstandardized), location, study objectives, design , the length of follow-up (if applicable), the sampling method, sample composition and size, the assessment of asthma severity, the types of medication used, the assessment of relevant outcomes, and population demographics.After the 'extraction phase,' appropriate data were selected and grouped together to strengthen the outcomes measured ('pooling phase'). Key criteria such as the design and sample base were used to group together relevant surveys so as to address the most important outcomes and the incidence of those outcomes (expressed as ranges). At this stage it was clear that substantial differences in studies – which included differences in national or international scope, design, setting, timing, sample bases, and objectives – precluded a formal meta-analysis. Thus, while it was statistically inappropriate to combine results from these surveys, general comparisons were carefully undertaken where there were no confounding factors. A list and overview of the design of surveys reviewed is provided in Table The review was further classified according to a structured set of most relevant outcomes identified ('assessment phase'). The following patient outcomes were assessed: understanding of the disease (etiology), perception of asthma control, satisfaction with treatment, compliance with therapy, and impact on patient and family QoL. Childhood asthma was examined separately to identify any trends specific to this population, although pediatric data were also included in the wider patient perspective assessment. At the HCP level, the same outcomes that were assessed in patients were evaluated when available; this allowed for a comparison of similarities and differences in perception between HCPs and patients on these issues.The 24 surveys reviewed included a total of 66,450 subjects from a total of 24 countries; of this number, 57,817 were patients  and 8,633 were HCPs . Table 1A few surveys contained feedback from patients that addressed their disease understanding. In TARGET , 38% of Eight surveys ,25,27,32Perhaps not surprisingly, some surveys provided data to indicate a poor level of control while others indicated a high level of suboptimal therapy. One survey, comparing treatments across Europe, discovered a complete absence of treatment in <20% to 70% of patients from country to country (70% in Estonia) . In a USEighteen surveys, with a combined patient population of approximately 34,000, reported data on patient satisfaction and were pooled for descriptive analysis ,19-28,32Fourteen surveys -21,26,27Eleven surveys that included approximately 34,700 patients assessed varied lifestyle-related endpoints ,25,27,32Although one survey showed that lifestyle was affected irrespective of disease severity , overallFifteen surveys ,27,30-32Over 8,600 HCPs were included in the surveys reviewed ,27,29,30Of broad interest was the attitude towards using continued or increased doses of ICS compared with newer therapies. Again, in the TARGET survey , althougPatients reporting symptoms of asthma often reported that their asthma was well controlled, while in combined patient/HCP surveys their HCP reported that it was not well controlled ,17,20,21There was a greater agreement in the views of patients and HCPs relating to long-term therapy. In one survey , 57% of The present review of 24 patient surveys indicates that patients often experience high levels of asthma symptoms even while receiving asthma therapy. Patients' perceptions of asthma control and prevalence of symptoms were often mismatched: patients who considered their asthma well controlled still reported daily symptoms. Furthermore, while many patients were conscious of the clinical factors indicative of lack of symptom control , many failed to fully understand the impact of the disease on their everyday life, and patient awareness did not necessarily translate into an understanding of the need to control symptoms. A substantial majority of patients appeared to tolerate suboptimal treatment. In addition, the survey results suggest that asthma may have a substantially underestimated impact on QoL, expressed in terms of difficulty in breathing, ability to exercise, and quality of sleep.Adherence failure was common because of a variety of factors and not just because of concerns about drug side effects. This was often compounded by a low expectation of receiving an appropriate therapy or of having a positive encounter with the HCP. Surprisingly, physicians were also often unaware of the extent of their patients' poor adherence or misuse of treatments. Moreover, patients often underreported their symptoms and severity, which in turn could have led to misclassification and undertreatment.Overall, the results of the present review indicate that many patients lack an understanding of the importance of inflammation in asthma, and few are aware of the anti-inflammatory effects of treatments. A recent review of the Asthma Insights and Reality surveys referred to the low level of use of anti-inflammatory medication, the suboptimal control of asthma, and the consequent deterioration in the lifestyle of patients . These rOverall, pediatric patients seemed to be better managed than adults with asthma, not simply because there tends to be a stronger emphasis on childhood asthma in most countries, but also because caregivers and parents seemed to show greater involvement in managing their children's disease and were highly conscious of drug safety issues. The surveys did, however, highlight parents' confusion about, and their lack of understanding of, childhood asthma and its therapies. A number of parents (approximately 40%) in one survey regarded asthma in their children as a stigma and were in potential denial of their children's condition . This clAs with the adult populations, there was a strong difference between perception of control (by children and their caregivers) and the practical issues of symptom management. In general, children utilized a proportionately greater share of resources than adults . A recenA common theme that emerges from many of the surveys is the dissatisfaction and poor outcomes seen with asthma controller medications. Among the numerous reasons for this are concerns over safety, poor efficacy, and poor adherence. Encouragingly, both patients and their HCPs generally seemed to agree within the same survey that there was a need to use medications with fewer side effects and fewer long-term complications. There was, however, some evidence of differences in opinion among physicians on the best strategy for long-term and more complete asthma control.Our report evaluates asthma management from the patients' perspective. The 24 surveys reviewed illustrate the burden of asthma in patients and attitudes toward its diagnosis and treatment among patients as well as HCPs, including asthma specialists, pediatricians, general practitioners, pharmacists, and nurses. A limitation of the present review is therefore that it constituted a qualitative analysis and hence could be considered a subjective appraisal. A true quantitative meta-analysis was not possible because of the variety in study designs, as well as in populations and outcomes studied. Moreover, the selection of studies was not fully comprehensive; instead, we chose to include a varied selection of surveys to provide as balanced a perspective as possible. The surveys originated in many different countries in Europe and North America and were conducted by different sponsors, including three different pharmaceutical companies. Nevertheless, we believe some important and consistent messages emerge that should influence better asthma management in the future.Findings of the present review of asthma surveys suggest that patients often understate their symptoms, tolerate poor symptom control, have low expectations of therapy, possess meager knowledge of correct drug usage, and display insufficient adherence to therapy. Among HCPs, there is evidence of an inadequate understanding of disease etiology and poor or unstructured communication with patients, resulting often in inaccurate assessment of disease severity. With the increasing incidence of asthma, it is important to address these many issues as a matter of priority. In particular, asthma care could be made substantially better by improving the education of patients regarding the nature of the disease (as one primarily of inflammation) and optimizing the use of existing medical systems and treatments.HCP = healthcare provider; ICS = inhaled corticosteroids; QoL = quality of life.STH has received fees for lectures from Novartis and Merck Sharp & Dohme and is a consultant for Novartis, MRL, Almiral Prodesfarma, Rotta Pharm, Cambridge Antibody Technology, Amgen, Wyeth, UCB/Celltech, Avontec and Synairgen. DP has received honoraria for speaking at sponsored meetings from the following companies marketing respiratory products: 3 M, Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, IVAX, Merck Sharp & Dohme, Novartis, Pfizer and Schering-Plough. DP has also received honoraria for advisory panels with 3 M, Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, IVAX, MSD, Novartis, Pfizer and Schering-Plough. DP or his research team have received funding for research projects from 3 M, Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, IVAX, Merck, Sharp & Dohme, Novartis, Pfizer, Schering-Plough, Viatris. EV has received speaker's honoraria from Merck & Co.


IL4 and IL4RA genes have been described. Particularly, -33C>TIL4 and 576Q>RIL4RA SNPs have been independently associated to atopy and asthma. The purpose of this study was to analyse these polymorphisms in a population of patients with a well-characterized asthma phenotype.IL4/IL4RA pathway plays an important role in atopy and asthma. Different polymorphisms in IL4 was studied with TaqMan assay and 576Q>RIL4RA by PCR-RFLP technique. Hardy-Weinberg equilibrium was analysed in all groups. Dichotomous variables were analysed using χ2, Fisher exact test, Monte Carlo simulation test and odds ratio test. To model the effects of multiple covariates logistic regression was used.A total of 212 unrelated Caucasian individuals, 133 patients with asthma and 79 healthy subjects without symptoms or history of asthma or atopy and with negative skin prick tests were recruited. Lung function was measured by spirometry and asthma was specialist physician-diagnosed according to the ATS (American Thoracic Society) criteria and classified following the GINA  guidelines. Skin prick tests were performed according to EAACI recommendations. -33C>TIL4 and 576Q>RIL4RA polymorphisms were compared. However, the T allele of the -33C>TIL4 SNP was more frequent in patients with persistent asthma. Multivariate analysis adjusted for age and sex confirmed that carriers of allele T had an increased risk of persistent asthma . Analysis of combination of polymorphisms showed that patients carrying both the T allele of -33C>TIL4 and the A allele of 576Q>RIL4RA had an increased risk of asthma. This association was particularly observed in persistent asthma .No statistically significant differences between the group of patients with asthma and the controls were found when the allele and genotype distribution of -33C>TIL4 and the A allele of 576Q>RIL4RA with asthma. This genetic variant was more frequently observed in patients with persistent asthma. As long as this study was performed in a small population, further studies in other populations are needed to confirm these results.Our results show a trend of association between the genetic combination of the T allele of -33C>T IL4 gene has been mapped to chromosome 5q31 where asthma and atopy have also been linked . Multivariate analysis of the genotypes adjusted for age and sex confirmed a trend of association of -33C>TIL4 polymorphism with an increased risk of persistent asthma . No differences were found in the group of subjects suffering allergic asthma compared to controls. Analysis of the total IgE levels failed to reveal any significant difference (p = 0.22), even when separate analysis for each gender was performed (data not shown).Characteristics of patients and controls are shown in Table IL4RA arginine allele (G) was found at a frequency of 0.16 in patients with asthma versus 0.21 in healthy subjects .576RIL4 / 576Q>RIL4RA combinations between the group of patients with asthma and the group of controls   = 0.045]. Patients who were carriers of both the T allele of -33C>TIL4 and the A allele of IL4RA had an increased risk of atopy  . Patients who carried both the T allele of -33C>TIL4 and 576Q>RIL4RA polymorphisms in a well-characterized Spanish population of patients with asthma and in a healthy control population. Controls were older than patients allowing a longer period for asthma diagnosis to be made. When we analysed the -33C>T polymorphism independently, we did not detect significant differences in allele or genotype frequencies between the group of patients and the group of controls. Nevertheless, we observed a higher incidence of the T allele of -33IL4 in the group of patients with asthma  declare that they have no competing interests.MIG participated in the design of the study, carried out the molecular genetic studies, performed the statistical analysis and drafted the manuscript.IDG participated in the design of the study, coordinated the clinical aspects of the study, helped to perform the statistical aspects and to draft the manuscript.EL participated in the clinical aspects of the study.EM participated in the clinical aspects of the study.FL participated in the design and coordination of the study.RGS conceived the study, participated in its design and coordination and helped to draft the manuscript.All authors have read and approved the final manuscript.


We have previously demonstrated that patients with Crohn's disease (CD) of long duration have signs of autonomic neuropathy. The aim of this study was to examine whether autonomic neuropathy is an early manifestation of CD, or a sign appearing late in the course.Twenty patients, median age 40 years, with a short duration of CD were included. Examination of autonomic reflexes included heart rate reaction to tilt  and heart rate variation to deep-breathing (expiration/inspiration index-E/I). Seven years later the same examinations were repeated, and in addition we examined the vasoconstriction response to indirect cooling by laser Doppler (vasoconstriction-index – VAC-index). The results were compared with healthy individuals.There was no difference in the blood pressure between controls and the patients with CD at rest, but eight minutes after tilt, the systolic blood pressure was lowered in patients compared to controls, both at the first assessment (p = 0.016) and after seven years (p = 0.042). The change in systolic blood pressure between rest and eight minutes after tilt was not significant at the first assessment, while a significant change compared to controls was observed seven years later (p = 0.028). This indicates a progressive dysfunction. There were no differences in E/I, AI, BI or VAC indexes between patients and controls.Patients with CD suffer from autonomic neuropathy early in their disease, suggesting involvement of many different organ systems in this entity. Crohn's disease (CD) is a chronic inflammatory condition that may involve the entire gastrointestinal tract. Both infectious agents and autoimmune mechanisms have been proposed as aetiological factors. The inflammatory process is transmural and extra intestinal inflammatory manifestations are common, suggesting a systemic character of this disorder .We have earlier described the presence of autonomic neuropathy in both CD and ulcerative colitis (UC), although more prevalent in CD ,3. ParasThe former studies examined patients who had suffered from their disease for many years ,3. We noTwenty patients 14 women) with CD of the small intestine and/or colon were invited to participate in this study examining autonomic nerve functions. The median age was 40 years , and the median duration of disease 44 months . The diagnosis was based on established clinical, radiological and/or endoscopic and histological criteria . Mann-Whitney U test was used for comparisons between the controls and the patients at two different occasions. Fishers' exact test was used to compare the frequencies of findings. As 25% of the patients were lost for follow up, no longitudinal calculations were performed. P < 0.05 was considered to indicate statistical significance.This prospective study was approved by the Ethics Committee at Lund University. All patients gave written informed consent before entering the study.There was no difference in systolic blood pressure between controls and patients during rest. In the controls, the systolic blood pressure was equal at rest and one and eight minutes  after tilt. In contrast, patients with CD had lower blood pressure eight minutes after tilt at the first assessment compared to controls . At the second assessment after seven years, there was a tendency to lower blood pressure one minute after tilt compared to controls , and after eight minutes, the blood pressure was further lowered .When calculating the change in systolic blood pressure between rest and after one and eight minutes, this did not differ at the first assessment compared to controls (data not shown). However, at the second assessment the systolic blood pressure tended to differ after one minute (p = 0.063), and the change was significantly different compared to controls after eight minutes Fig . Thus, tThere were no differences in E/I or VAC indexes between controls and patients with CD, neither at the first nor at the second assessment (data not shown).The present study disclosed an impaired ability to keep the systolic blood pressure after tilt in patients with a short duration of CD. This is in accordance with early sympathetic neuropathy . AutonomIn CD, proliferate and injurious changes have been described in the enteric smooth muscles, enteric nerves and interstitial cells of Cajal (ICCs) -19. We hAs the ENS is part of the autonomic nervous system, damage to ENS could reflect a general damage to the nervous system. The current findings are in accordance with a recent description of sympathetic neuropathy in patients with chronic intestinal pseudo-obstruction (CIPO) , a diseaAlthough the heart frequency and the diastolic blood pressure increased, the systolic blood pressure was lowered after tilt. VAC index, which also reflects the sympathetic nervous system , was witThe bi-directional brain-gut pathways transmit environmental signals to the intestine, and in the same way signals from the intestine to the brain. Many different signals from the central nervous system, e.g. stress, could thus modulate inflammatory bowel diseases . In addiIt should be noted that nobody of our patients with CD had classical symptoms of autonomic neuropathy , althougOur data suggest that autonomic sympathetic neuropathy is an early systemic feature of CD independent of disease activity. The neuropathy was slightly more pronounced after seven years and this progressive course is consistent with the more pronounced autonomic neuropathy manifested by abnormal indexes previously demonstrated in patients with CD of longer duration .The authors declare that they have no competing interests.BO participated in the design of the study, recruited subjects, financed the study and drafted the manuscript. GS and SL participated in the design of the study, and participated in drafting of the manuscript.The pre-publication history for this paper can be accessed here:


Incomplete drug regimen compliance (DRC) and white-coat hypertension are two of several possible causes of uncontrolled hypertension. Therefore the aim of the present study was to compare DRC in hypertensives treated with combination therapy whose blood pressures (BP) were controlled vers. uncontrolled after 4 weeks of self-monitored BP measurement. To observe the consequences in uncontrolled patients of switching one drug of the combination therapy to candesartan/HCTZ (16 mg/12.5 mg) with and without a compliance intervention program.Self-and ambulatory-monitoring of BP were done with upper arm oscillometric devices. Patients' dosing histories were compiled electronically (MEMS(c), AARDEX). Patients with office blood pressure (OBP) >140/90 mmHg despite combination therapy were begun on MEMS monitoring and self BP measurement for 4 weeks of run-in. Of 62 such patients, 18 (29%) patients were normotensive according to self BP measurement and ambulatory BP measurement at 4 weeks (Group A); in the remaining 44 still uncontrolled patients, candesartan/HCTZ was substituted for one of the combination therapy drugs, with half these patients receiving passive compliance monitoring (B) and half a DRC intervention program (C). All groups were then followed for 8 weeks.DRC before week 4 was significantly higher in A than in the uncontrolled patients (B&C). DRC was stable during run-in A, but declined in B and C. DRC after week 4 was not different in the three groups and stayed constant over time. DRC during weekends was lower than during weekdays in all groups.In group A no significant change in blood pressure was observed with all three methods of BP measurements. In groups B and C significant reductions of systolic and diastolic BP were observed for ABPM and SBPM. After the change to candesartan/HCTZ in B&C ambulatory 24-h-BP (ABPM) was normalized in 39% of patients.Normalization of BP was associated with superior drug regimen compliance in previously uncontrolled patients treated with a combination drug regimen. Switching still-uncontrolled patients to candesartan/HCTZ significantly improved BP control and stabilized a declining DRC. Understanding and optimizing the management of hypertension is complicated by the lability of blood pressure, the sources of which include (a) white-coat effects, (b) variable exposure to prescribed antihypertensive drug(s), created by patients' variable but infrequently measured compliance with prescribed dosing regimen(s), (c) different magnitudes and time-courses of action of the many antihypertensive drugs, each of which has its own characteristic pharmacokinetic and pharmacodynamic behavior, (d) diurnal fluctuations in blood pressure, which may exceed in magnitude the hypotensive effects of antihypertensive drugs.A further disappointing finding has been pharmaco-epidemiologic data showing a high proportion of treated patients who discontinue treatment for no clear reason within some months or a year or two after the start of treatment ,2. This Candesartan cilexitil (Candesartan) is a highly selective and long acting AT1 receptor blocker with excellent blood-pressure lowering efficacy and a prolonged duration of antihypertensive efficacy exceeding 24 hours. In a "missed dose" study by Lacourcière and Asmar the duration of action of candesartan suggested that this AT1 receptor blocker may provide added confidence of therapeutic coverage in many patients who may not be 100% compliant with their once-daily medication regimen .The realization of such pharmaceuticals has, however, not solved either the compliance or the persistence problems . We haveAgainst that background, the present study was designed as a pilot study in a group of longtime treatment-resistant hypertensives, to explore some aspects of the respective roles of poor compliance with prescribed drug regimens, persistent unresponsiveness to correctly administered drug, and several modest interventions – a change in one of the prescribed drugs, use of ambulatory blood pressure monitoring, informing patients that their dosing histories were being continuously compiled, and some feedback to patients of both blood pressure data and dosing history data.Figure a. Definition of normal values for office, SBPM and ABPM and target BPsb. Prognostic implication of uncontrolled hypertensionc. Effect of non-compliance on control rated. Correct use of SBPMIn contrast, Group B was managed in the usual manner, with dosing history data being compiled by a standard, non-interactive MEMS Monitor, but without any special effort being made to improve the patients' compliance.Patients were consecutively recruited from the outpatient department of the Medizinische Poliklinik. Patients were refered to our department by GPs for resistant or difficult to treat hypertension. All patients gave informed consent to participate in the study and were informed about the function of the MEMS system. The University of Bonn issued a positive ethical vote on the study.®, AARDEX Ltd.) containers. The MEMS system comprises an electronic pill-bottle cap embedding a microship that creates an electronic time-stamp upon opening and closing the bottle. These time-stamps comprise a complete dosage history. Mems caps may also include a LCD display that reminds the patient the number of pills taken since the beginning of the day. In this article, the term interactive MEMS refers to the devices with screen displays. The recorded data can then be downloaded to a personal computer using Powerview software (Aardex Ltd.). This software offers features to visualise and compute basic individual statistics. Adherence to Candersartan was assessed using MEMS devices over the course of the study. Both interactive and non-interactive devices were used depending on the intervention group.Candersartan was dispensed in Medication Event Monitoring System (MEMScod) and the percentage of prescribed number of doses taken (tac).The quality of execution of the prescribed drug regimen is called 'compliance', defined as 'the extent to which the patient's dosing history corresponds to the prescribed regimen' Fig. . The lenSelf measurement was performed with a validated, oscillometric upper arm device, A&D UA-767 [Ambulatory 24-h BP measurement was done with the "CardioTens-01"  device , which mThe definitions of controlled hypertension are: self-measurement <135/85 mmHg, office <140/90 mmHg, ABPM (whole 24 h period) <130/80 mmHg. We decided to work on ABPM since this technique has important prognostic value, especially in patients with refractory hypertension [® version 6.2. BP values are expressed as means+S.D. In case of multiple comparisons between groups, a Bonferroni's correction of the significance level has been applied.The non-parametric Wilcoxon test was used to compare adherence distribution between groups. Comparison of binary time series were realized using a logistic regression where dependence among observations from a same patient over time was taken into account through a conditional approach. Comparisons of BP values were performed with the t-test for comparison between baseline and week 12. All significance tests are two-sided and statistical significance is set at 5%. All analyses are performed using the S-plusSample size was calculated to detect a 5 mmHg difference in systolic ABPM at 90% power and p < 0.05 in 20 patients.Sixty-two patients with essential hypertension and OBP ≥ 140/90 mmHg, despite combination therapy, were enrolled . After 4 weeks of run-in, 18 of these (29%) were normotensive at 4 weeks, and, on that basis, were designated Group A. For the remaining 44 evaluable, still-uncontrolled patients, candesartan/hydrochlorothiazide was substituted at week 4 for one of the previously prescribed combination therapy drugs. The choice of drug was left to the discretion of a experienced hypertension specialist. These 44 patients were randomized between group B (n = 20), to continue receiving passive compliance monitoring, and Group C (n = 24), to receive an intervention program designed to improve drug regimen compliance. Group B had 20 evaluable patients and C had 24. All groups were then followed for 8 weeks. The characteristics of patients with different antihypertensive drugs used at the beginning of the study are presented in table cod) and the percentage of prescribed number of doses taken (tac). Those quantities were computed for each patient during the two phases of the study. Table We consider simple statistics to summarize the patient's compliance history. The statistics used in this context are the percentage of days with correct intake (Zij indicating whether yes (1) or no (0), at least the prescribed number of doses were taken on day j by patient i. This coding retains much of the temporal structure in the individual patterns, but not exact times of drug doses [The aim of this section is to describe the evolution of an informative measure of adherence in randomized treatment groups. Because adherence to prescribed therapy measures the extent to which a person's behavior coincides with medical advice, it covers both a behavior and a measure. One factor influencing the other delivers raw data that have a complex structure with unusual correlation patterns of dosing intervals, and it is not obvious how to analyze these patterns. Rather than study detailed patterns, we summarize the adherence pattern in a sequence of binary data ug doses . The obsThe observed proportion of good compliers on each separate day after week 4 visit is presented in Figure Table The change in blood pressure between visit week 4 and visit week 12 is shown in the figure For SBPM the mean values 14 days preceding week 4 visit are compared with the 14 days preceding week 12 visit are compared. For ABPM the respective values of the last day of run-in and the last day of week 12 are compared. As expected in group A with unchanged medication no significant change in blood pressure was observed with all three methods. In groups B and C significant reductions of systolic and diastolic BP were observed for SBPM and ABPM.The blood pressure lowering effect of substitution by Candesartan/HCT was most pronounced as assessed by systolic OBPM  whereas diastolic OBPM reduction did not change significantly.The BP lowering effect resulted in normlization of ABPM in 39 % of patients in group B and 39% of patients in groups C. The confounding created by white-coat effect is illustrated by the data from Group A: at week 12, 80% were uncontrolled by OBP, whereas only 17% were uncontrolled as assessed by ABPM.At the end of the study 53% of all patients included  had normal ABPM values, i.e. <130/80 mmHg for the whole 24-h period.The average number of antihypertensive drugs before intervention (week 4) were 2.8+0.6, 2.8+0.9 and 2.8+0.9 for groups A, B and C respectively. The mean number of drugs after intervention significantly increased to 3.7+0.8 and 3.6+0.9 in groups B and C respectively.An overall result of this study was that the various maneuvers executed between the start and end of the study resulted in the normalization of blood pressure in 53% of the patients who had been persistently hypertensive by OBP measurement despite treatment with multiple drugs. The various maneuvers included: start of both home blood pressure monitoring and drug regimen compliance monitoring at week 0, exclusion of uncontrolled hypertension caused by a white-coat effect, change of the drug regimen in Groups B and C at week 4, and the commencement of a compliance-enhancement program in Group C at week 4. In the persistently hypertensive groups B and C, 39% achieved normalization of blood pressure. In the present study, a number of factors made it impossible to deduce which of the various maneuvers, including compliance-improvement, played the dominant role in the normalization of blood pressure, nor is it evident what sorts of reductions in the number of drugs or doses prescribed might be possible in correctly dosing former poor compliers, without loss of control over blood pressure.A fortunate aspect of the present study is that the maneuvers performed were fairly simple and cost effective, and without discernible hazards, so that repetition with better collection of data and simplified designs may allow identification of the most important maneuvers.Compliance in week 0–4 was monitored with up to 3 MEMS boxes in individual patients. Since – as in previous studies – no difference could be observed between 1 or more MEMS boxes, we decided to continue on 1 MEMS box for Cande/TZDDuring the run-in period, the percentage of prescribed doses taken, which is one of several ways to express drug regimen compliance, fluctuated to a slight extent, but remained essentially constant in Group A. In contrast, the patients who were destined to comprise Groups B and C showed a more or less continuous decline in percentage of prescribed doses taken, from the mid-point to the end of the 4-week run-in period, during which time the mean percentage of prescribed doses taken declined from 93% to 62%.Remarkably, compliance in Groups B and C improved immediately following the visit at week 4 and continued, as shown in Figure A notable finding was a substantially higher incidence of omitted doses on weekends (Fridays-Saturdays-Sundays) than on weekdays (Mondays thru Thursdays). This phenomenon was also reported in a previous work by Mallion et al. . This prFollowing the change to candesartan/HCTZ in Groups B&C significant BP reductions could be observed with all three methods of BP monitoring. Since ABPM is more useful than OBPM in stratifying cardiovascular risk in patients with refractory hypertension, we used the normalization criteria of ABPM. It is remarkable that a normalization rate of 39% was achieved as monitored by ABPM in groups B&C. This beneficial finding is in keeping with results of prior studies, and may in part be due to the relatively long duration of action of candesartan, which could be expected to have the effect of allowing antihypertensive action to persist in the face of delayed or omitted doses -14. The Drug regimen compliance after week 4 was not different in the three groups, staying essentially constant over time, very close to correct dosing each day, with of course the exception of the 'weekend effect', the pressure correlates of which we did not explore. Relatively long-acting antihypertensive agents, e.g., candesartan, can 'forgive' dose omissions occurring on weekends, whereas relatively short-acting drugs, that cannot maintain pressure control for at least 48 hrs after a last-taken dose, cannot .Clearly the transactions between investigative staff and patients had substantial though variably sustained impact. We do not know – and it is an important omission that should be avoided in future studies – what the dosing histories and thus the compliance levels were in the period prior to the start of the run-in period. One naturally wonders if it were not generally poor in many or most of the patients before the start of the study, whereupon the first measurements showed it to be high in all patients, perhaps a forerunner of the abrupt jump in compliance that we see in Groups B and C immediately after the week 4 visit. Perhaps – but we can only speculate and take the point in designing future studies – the patients who were to comprise Group A were, prior to the start of the study, poorly compliant, but received enough motivation from the various maneuvers made at the start of the study, so that their compliance rose and their blood pressures concomitantly normalized, where they remained throughout the 12-week study. A high priority, therefore, is to master – as some investigators have ,17 – theFor reasons that this study does not reveal, the week 4 visit restored average compliance in Groups B and C to the same high range it had in the first 2 weeks after of the initial visit at the start of the study. One naturally wonders whether maneuvers begun at the start of the study, 4 weeks previously, had not had a similar effect, akin to that which we see after week 4, of improving a previously unsatisfactory compliance. It is also a matter of conjecture about which of the various maneuvers uniquely associated with the conduct of the study played the biggest role in (a) achieving a sustained increase in compliance in Groups B and C, and (b) achieving blood pressure control in a fraction of the patients in Groups B and C.Another limitation of the study was the rather short duration of the study. It is well known that long term, "real life " compliance may not be reflected by short observation periods 1 or 2 months.This study demonstrated blood pressure normalization in a 53% of previously uncontroled hypertensives. Clearly, the use of ABPM and SBPM were helpful in identifying white-coat effects. The mechanisms for this improvement are not clear, but each of the maneuvers that preceded this improvement are simple, safe, easily applied, and relatively economical. Further work, taking cognizance of the shortcomings of the present study, can probably differentiate the more from the less effective of the maneuvers, and help improve the proficiency of their use.OBP: Office blood pressureSBPM: Self blood pressure measurementABPM: Ambulatory 24-h blood pressure measurementMEMS: Medication Event Monitoring SystemInteractive Mems: Mems with screen displayThis study was supported by AstraZeneca Germany.Eric Tousset is an employee of Aardex, the company manufacturing the monitors used in this study.All other authors declare that they have no competing interests.TM conceived of the study, and participated in its design and coordination and drafted the manuscript. ET performed the statistical analysis of compliance and blood pressure parameters. VH participated in the design of the study and coordination. SU recruited the patients, supplied blood pressure measurements and electronic pill boxes, hold the structured hypertension teaching program and drafted the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Heart rate variability (HRV) is known to be impaired in patients with congestive heart failure (CHF). Time-domain analysis of ECG signals traditionally relies heavily on linear indices of an essentially non-linear phenomenon. Poincaré plots are commonly used to study non-linear behavior of physiologic signals. Lagged Poincaré plots incorporate autocovariance information and analysis of Poincaré plots for various lags can provide interesting insights into the autonomic control of the heart.Using Poincaré plot analysis, we assessed whether the relation of the lag between heart beats and HRV is altered in CHF. We studied the influence of lag on estimates of Poincaré plot indices for various lengths of beat sequence in a public domain data set (PhysioNet) of 29 subjects with CHF and 54 subjects with normal sinus rhythm.-5, 0.002, 3.5 × 10-5 and 0.0003, respectively). This curvilinearity was lost in patients with CHF even after exploring sequences up to 50,000 beats .A curvilinear association was observed between lag and Poincaré plot indices  in normal subjects even for a small sequence of 50 beats (p value for quadratic term 3 × 10Since lagged Poincaré plots incorporate autocovariance information, these analyses provide insights into the autonomic control of heart rate that is influenced by the non-linearity of the signal. The differences in lag-response in CHF patients and normal subjects exist even in the face of the treatment received by the CHF patients. In thhe first . It has he first . Therefohe first .et al [Heart rate variability analysis provides a noninvasive means to assess the autonomic status of the heart -8. Underet al  argue thTherefore, we hypothesized that the lag-response patterns of linear and non-linear Poincaré plot indices would be different in a diseased heart as compared to a normal heart. To test our hypothesis, we compared long-term ECG recordings of a group of CHF subjects with those of normal subjects. We also explored whether linear versus non-linear indices of HRV behaved differentially with respect to the lag. Finally, we compared the lag-responses of CHF patients and normal subjects in light of the fact that heart rate variability may have been potentially restored by the pharmacologic therapy in the CHF patients. Thus, we suggest an alternative analytic strategy that has the potential to provide unique insights into the pathophysiological basis of CHF.We used the PhysioNet internet resource which is a large repository of various physiologic signals including electrocardiograms recorded by a 24-hour Holter monitor ,18. FromThe databases in the PhysioNet repository contain 24-hour Holter ECG recordings in two data formats; unaudited beat-wise annotations sampled at a frequency of 128 samples per second and the corresponding header identification information. The WFDB software package provided by the PhysioNet resource was used to extract beat-wise R-R intervals. We used the "ann2rr" command to extract a sequence of up to 50,000 normal beats (approximately 12 hours of ECG recording) to estimate the normal-to-normal  intervals in seconds.The standard measures of heart rate and its variability in the time domain are considered linear measures . These im-lagged R-R intervals. Thus, we were able to estimate m-lagged deltas and their standard deviations (SDLD). In the special case of 1-lagged beats, the mean deltas and SDLD are respectively equal to mean successive delta and SDSD. We, then, estimated the SD1 and SD2 for each of the m-lagged beat sequence. Thus, we included the following four indices in our analysis: SDLD, SD1, SD2 and SD1/SD2 ratio.For our analyses, we included only those indices that mathematically depend on the lag. As Mean RR and SDRR are theoretically independent of lag, we did not include these indices for studying the lag-response. However, mean deltas and SDSD can be appropriately generalized to measure the lag response. For instance, we estimated deltas as the difference between the Controversy exists with regard to the period of time for which ECG recordings should be monitored to best capture the HRV dynamics. While some researchers maintain that recordings less than 18 hours are insufficient , others m-lagged Poincaré plots can describe the autocovariance function, the autocovariance function monotonically decreases with increasing lag for values of lags less than 10, and that the current beat influences only about six to eight successive beats in the context of a short range influence, we expected a pattern of lag-response which is stronger at the lower values of lag and which attenuates with increasing lag. In normal subjects, therefore, we expected a curvilinear relationship that explains variations in Poincaré plot indices on the basis of lag. To test for curvilinearity we used a quadratic relationship model and plotted the estimates of SDLD, SD1, SD2, and SD1/SD2 ratio against lag. We then fitted a second-order polynomial curve using the least-squares method. We assessed the model-fit using R2 values. We then compared the average coefficients of the quadratic term in the second-order polynomial equations in subjects with and without CHF.Considering the facts that m-lagged Poincaré plot indices in CHF and normal groups by using Mann-Whitney rank sum test. To study the potential contribution of varying beat sequence length to estimates of the Poincaré plot indices, we used the non-parametric method of Spearman's correlation coefficient (ρ). The curvilinearity of the lag-response was assessed by using a second order polynomial regression and the model-fit was assessed using the R2 value in order to quantify the amount of variation explained by the quadratic lag-response of the Poincaré plot indices. We wrote dedicated routines in Visual Basic® for estimation of m-lagged Poincaré plot indices. Then, we used Stata 7.0® for statistical analysis. For all statistical analysis, we assumed statistical significance as p < 0.05.We compared the linear and non-linear -5). In spite of a non-significant difference between CHF patients and normal subjects for both SD1 and SD2 in sequences less than 5000 beats in length, the ratio of these two indices (SD1/SD2) in the same sequences showed a highly statistically significant difference with the ratio being consistently higher in CHF patients (p ≤ 2.5 × 10-6) 2 range 0.0003–0.094) in CHF patients using the smallest sequence length of 50 beats. In striking contrast, smooth second-order polynomial curves explained more than 99 percent of the variance in the estimates of these indices on the basis of lag in the normal subjects. We therefore compared the mean values of coefficients of the quadratic term in CHF patients versus that in normal subjects. It can be observed from Table We analyzed the association between Poincaré plot-related estimates of heart rate variability and lag for varying beat sequence lengths. Figure We again examined if the increased HRV seen in the CHF patients (described in the previous section) confounded our interpretations of the lagged Poincaré plot analyses. We observed that  A large proportion of the CHF patients exhibited patterns of complex Poincaré plots; ii) It is possible that the differential distribution of age, gender, socioeconomic status and other unknown parameters in the comparison group may have confounded the observations on increased heart rate variability in CHF subjects; and iii) all the CHF patients in this study were receiving long-term digoxin therapy ,20 whichet al reported that depression of long term variability is a predictor of mortality [Furthermore, though SD1 and SD1/SD2 ratios were higher in CHF patients as compared to normal subjects, SD2 (an index of long-term variability) was higher in the normal subjects for beat sequences 500 and above. This is consistent with two sets of observations: first, CHF patients are more likely to have a high degree of sinus arrhythmia that is not of respiratory origin, that is, they are more likely to have sudden jumps in the N-N interval; and second, a study by Huikuri ortality . Thus, CIn summary, despite the presence of these limitations, our study provides strong evidence for the loss of curvilinearity in the lag-response of Poincaré plot indices in CHF patients even after receiving long-term therapy and even in cases in which some traditional measures of HRV are similar to those seen in normal individuals. We propose that these approaches of analysis can be used to improve the time-domain analysis of ECG signals and can enhance the diagnostic and prognostic indicators of CHF.1. CHF – Congestive Heart Failure2. ECG – Electrocardiogram3. HRV – Heart Rate Variability4. RR – RR interval 5. SD1 – Standard Deviation 1 (long axis of ellipse fitted to Poincaré plot)6. SD2 – Standard Deviation 2 (short axis of ellipse fitted to Poincaré plot)7. SDLD – Standard Deviation of Lagged Deltas8. SDRR – Standard Deviation of RR intervals9. SDSD – Standard Deviation of Successive Differences10. pNN50 – percentage of beats with change in successive NN intervals exceeding 50 ms11. pNN20 – percentage of beats with change in successive NN intervals exceeding 20 ms12. SDNN – standard deviation of the NN intervalsThe author(s) declare that they have no competing interests.TPT conceptualized the study, performed the analysis of the data and wrote the initial and revised drafts of the manuscript. MLS contributed to the data analysis and the review and revision of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:This document contains supplementary tables 1–4. Supplementary Table 1 details characteristics of the subjects included in the present analysis. Supplementary Table 2 shows replication of analyses shown in Table Click here for fileThis file has hourly Poincaré plots for the 29 CHF patients.Click here for fileThis file has hourly Poincaré plots for the 54 control subjects.Click here for file


Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients  were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD. Cardiovascular diseases (CVDs) are the most important cause of death in patients with rheumatoid arthritis (RA). RA is associated with a significant increase in cardiovascular morbidity and mortality compared to the general population -7. A cleA complex element in the association between RA and cardiovascular risk is the use of antirheumatic medication. Patients with persisting disease activity require treatment with disease-modifying antirheumatic drugs (DMARDs) . There aDemographic, RA and CVD related data were collected from 613 RA patients by chart review. This sample of RA patients was randomly taken from the entire RA population registered in the Jan van Breemen Institute, a large rheumatology outpatient clinic in Amsterdam, the Netherlands. All patients fulfilled the American College of Rheumatology criteria of RA. Patients were recruited from time of diagnosis, between 1953 and 2002, onwards until March 2004, the end of the follow up period.A case control study of incident CVD was performed, comparing 72 patients with RA and CVD to 541 RA patients without CVD. CVD was evaluated from the time of diagnosis of the RA up to the time of the first cardiovascular event or until the end of the follow up period.CVD was defined as a verified medical history of coronary, cerebral or peripheral arterial disease. Coronary artery disease included a history of myocardial infarction, a coronary artery by-pass graft procedure, a percutaneous transluminal coronary angioplasty or ischemic abnormalities on ECG. Cerebral arterial disease was defined as a history of cerebral vascular accident (confirmed by a neurologist), a transient ischemic attack or a carotid endarterectomy. Peripheral arterial disease included an aneurysm of the thoracic and/or abdominalis aorta, a peripheral arterial by-pass operation and amputation of the (lower) leg. Assessed risk factors for CVD were age, male sex, hypertension, diabetes, hypercholesterolemia, and smoking habits. Hypertension, diabetes and hypercholesterolemia were considered to be present if patients received treatment for these conditions. Smoking habits were recorded as use ever versus never. All these variables were monitored throughout the entire disease duration.Comparisons between the various DMARD groups and between the RA patients with CVD and without CVD were performed using Students' t-tests and Mann-Whitney U-tests for continuous variables and Pearson's Chi-square tests for dichotomic variables.The dataset was categorized into groups according to the use ever of sulfasalazine (SSZ), hydroxychloroquine (HCQ) or MTX, either as monotherapy or as combinations of these drugs . The final group consisted of patients who never used any of the three major DMARDs; this resulted in a total of eight groups. These groups were chosen because SSZ, HCQ and MTX are the most commonly used drugs and well represented in our random sample of RA patients.Logistic regression modeling was used to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs) of CVD for the various DMARD groups simultaneously. In the regression analysis the group of RA patients who never used SSZ, HCQ or MTX was used as the reference group with a preset OR of 1.00.The first regression model corrected for age, gender, smoking ever and RA duration. Correcting for age, gender and smoking was done because these variables are known to be associated with CVD but not with the use of certain DMARDs. Correcting for RA duration was done because the chance for a patient to be treated with more than one DMARD increases the longer the duration of the disease. As an additional analysis prednisone use ever was added to this first model.In the second regression analysis we added the presence of hypertension, diabetes and hypercholesterolemia to the first model. Adding these known risk factors for CVD was done for two reasons. Firstly, because these risk factors could be over- or under-represented in certain DMARD groups and, therefore, falsely influence the cardiovascular risk for these groups. Secondly, correction for known cardiovascular risk factors was done to explore possible pathways by which the investigated DMARDs can influence cardiovascular risk; for example, a DMARD could increase the cardiovascular risk by causing hypertension and this increased risk would disappear after correcting for hypertension.A third analysis was done using the first model and adding the presence or absence of a positive rheumatoid factor test and erosions on radiographs. This enabled us to calculate the ORs for CVD associated with these two RA related variables.The three models described above were also used to explore if there was any dose dependency in the possible associations between the DMARD groups and CVD risk. Therefore, we determined the presence of interactions between any of the DMARD groups and the maximum used dosages, days of DMARD use and a cumulative variable. Because the maximum dosages of the different DMARDs are of different quantities  we calculated the percentage of the maximum dosages allowed by the Dutch and European medication agencies to be prescribed. For example, 30 mg is the maximum dosage allowed to be prescribed for MTX; therefore, if a patient only used 15 mg at the most, we used 50% as the maximum dosage in the calculations. This way we were able to compare the various DMARD dosages. As a cumulative variable we calculated the maximum percentage of the highest prescribable dosage multiplied by the years this DMARD was used.A p value of 0.05 or smaller was considered statically significant and all tests were performed using the SPSS 12.0 software package for Windows .The baseline characteristics of the RA patients with and without CVD in our study population are shown in Table Various RA and CVD related variables of the entire study population and the different DMARD groups are shown in Table ORs for CVD calculated for three models comparing the various DMARD groups to the RA patients who never used SSZ, HCQ or MTX are presented in Table The second model added additional correction for hypertension, diabetes and hypercholesterolemia to the corrections of the first model. This model revealed significant reductions in risk for CVD for the 'MTX and SSZ ever' and 'MTX, SSZ and HCQ ever' groups.The third model, correcting for the same variables as model 1 plus rheumatoid factor positivity and erosions, showed significant CVD risk reduction for the 'only MTX ever', 'only SSZ ever', 'MTX and SSZ ever' and 'MTX, SSZ and HCQ ever' groups. This third model quantified the ORs for having positive rheumatoid factor test and erosions on radiographs (OR 2.04 (95% CI 1.02 to 4.07) and OR 2.36 (95% CI 0.92 to 6.08), respectively), showing RA patients with poor prognostic signs to have an elevated risk for CVD.As an additional analysis we added the use ever of prednisone to the first model, giving an OR for CVD of 0.89 (95% CI 0.48 to 1.65), showing no significant association between corticosteroid use and the development of CVD.None of the calculated interactions between the DMARD groups and maximum dosages or the days of DMARD use reached statistical significance . Moreover, several interactions between the DMARD groups and the cumulative variable did reach statistical significance. In models 1 and 3 we found significant interactions for the 'MTX, SSZ and HCQ ever', the 'MTX and SSZ ever' and the 'SSZ only' groups. In model 2 just the 'MTX, SSZ and HCQ ever' group showed a significant interaction with the cumulative variable. All the observed interactions showed that the cardiovascular risk for these DMARD groups decreased when the cumulative DMARD exposure increased .The present study is the first showing a protective role of DMARD use for the risk of cardiovascular morbidity in RA patients. Furthermore, it demonstrates that rheumatoid factor positivity and joint destruction on radiographs both approximately double the risk for CVD.Earlier studies report on associations between DMARDs and cardiovascular mortality ,21, the Mechanisms by which DMARD use could influence the risk for CVD are poorly investigated. HCQ is reported to influence cardiovascular risk by lowering total cholesterol levels ,22. CortThe reduction of CVD-related morbidity in MTX treated patients is in line with the reduced CVD-related mortality in these patients as found by Choi and colleagues. The results of the present study suggest that the use of other conventional DMARDs, such as SSZ (but not significantly HCQ), is also associated with a reduction in the risk of developing CVD, which strengthens the hypothesis that reducing inflammation is of importance to reduce the risk of CVD. The relationship between inflammation and cardiovascular risk is furthermore underlined by the observation that rheumatoid factor positivity and joint destruction are associated with CVD. These findings stress the importance of aggressive pro-active treatment of RA, as this would not only be beneficial for the outcome of the patients' mobility but could also prevent co-morbidity such as CVD.There are some limitations to the present study. First, data were obtained by chart review; however, this was done systematically by one observer and classification of CVD was verified in source documents. Second, there is the possibility of 'confounding by indication', that is, more severe disease, in this case indicated by the presence of rheumatoid factor and erosions on radiographs, was associated with a higher risk of CVD; however, patients with these characteristics are also likely to receive more aggressive treatment with DMARDs, which were found to be associated with a cardiovascular protective effect. Therefore, confounding by indication may have biased the results towards null. We can not exclude entirely such a phenomenon; however, the reported associations between DMARDs and CVD risk remained present when variables of severity were included in the analyses.RA patients who are being treated with DMARDs, especially MTX, have a reduced risk for CVD in comparison with RA patients who do not use SSZ, HCQ or MTX. We hypothesize that treatment with MTX, and other conventional DMARDs to a smaller extent, is associated with less severe atherosclerosis through suppression of inflammation, which results in a decreased risk for CVD.Additional file 1 is a series of tables showing dose dependency in DMARD groups and association with CVD; and interaction between DMARD groups with the following variables: percentage maximum dose, days DMARD-use and cumulative dosage years.CVD = cardiovascular disease; DMARD = disease-modifying antirheumatic drug; HCQ = hydroxychloroquine; MTX = methotrexate; OR = odds ratio; RA = rheumatoid arthritis; SSZ = sulfasalazine; CI = confidence interval.The authors declare that they have no competing interests.VvH was responsible for the conception and design of the present study, data acquisition, analysis and interpretation and was involved in drafting the manuscript. MN was involved in the present study's conception, the interpretation of the data and revising the manuscript critically. JT was responsible for the study design and interpretation of the data and was involved in writing the manuscript, focusing on the statistical analyses. BD was involved in the design of the present study and gave his intellectual input during the drafting process. AV was also involved in the conception and design of the study, interpretation of the data and coordination of the drafting of the manuscript. All authors read and approved the final manuscript.Series of tables showing dose dependency in DMARD groups and association with CVD; and interaction between DMARD groups with the following variables: percentage maximum dose, days DMARD-use and cumulative dosage years.Click here for file