A survey of patients' attitudes to clinical research.

Every year hundreds of patients voluntarily participate in clinical trials across Ireland. However, little research has been done as to how patients find the experience. This survey was conducted in an attempt to ascertain clinical trial participants' views on their experience of participating in a clinical trial and to see and how clinical trial participation can be improved. One hundred and sixty-six clinical trial participants who had recently completed a global phase IV cardiovascular endpoint clinical trial were sent a 3-page questionnaire. Ninety-one (91%) respondents found the experience of participating in a clinical trial a good one with 85 (84.16%) respondents saying they would recommend participating in a clinical trial to a friend or relative and eighty-five (87.63%) respondents feeling they received better healthcare because they had participated in a clinical trial.

EUROASPIRE (European Action on Secondary Prevention through Intervention to Reduce Events) III--a comparison of Irish and European results.

The EUROASPIRE III audit was a Europe-wide study which took place in 2006/2007. The objective was to examine the control of risk factors in subjects with established cardiovascular disease. Here, we compare the Irish results to those of the other 21 European countries which participated. Control of blood cholesterol was significantly better in Irish participants, with 73% below the target of 4.5 mmol/l. Blood pressure control was less satisfactory in both Irish and European individuals, with an average of 52% of Irish participants not achieving blood pressure targets. Medication usage was high throughout, particularly anti-platelet agents, beta-blockers and, especially in Ireland, statins. Obesity figures were particularly high in Ireland and throughout Europe, with 82% Irish men and women either overweight or obese. Smoking figures in Irish women were also of concern, with 24% continuing to smoke. Cardiac rehabilitation attendance was particularly high in Ireland, with 68% attending; substantially higher than the European figure of 34%. In common with the rest of Europe, current control of body weight and blood pressure in Ireland is unsatisfactory and in need of increased consideration on the part of both patients and healthcare professionals.

Epidemiology and economics of statin use.

In 2006 the State supported the purchase of statins by some Euro 120 million for some 466,366 patients. While about 50% is for secondary prevention of heart disease a disproportionate number of women are receiving treatment for primary prevention. For proprietary agents the monthly cost was largely explained by price and dosage (mg/day) and the average varied from Euro 29.2 for rosuvastatin (11 mg), Euro 38.2 simvastatin (21 mg), Euro 39.1 atorvastatin (19 mg), Euro 42.7 pravastatin (21 mg) and Euro 31.8 for generic prava/simvastatin (21 mg). Generic substitution for pravastatin and simvastatin would save Euro 6.4m. Applying the drug prices corresponding in the United Kingdom would result in savings of some Euro 35m per annum. While the increasing use of statins is justified on cost benefit/analysis considerable savings could be made through choice of the more potent statins, a greater use of generics and a flatter dose price structure.

Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension.

Arterial stiffness is an independent predictor of cardiovascular events in a hypertensive population. Serum levels of matrix metalloproteinase (MMP)-9 are associated with arterial stiffness and predict cardiovascular risk. We investigated the role of MMP-9 polymorphism -1562C>T on blood pressure (BP) and arterial stiffness in a newly diagnosed hypertensive population. Untreated hypertensive patients (n=215, mean age 46+/-13 years) were studied. Supine BP, carotid-femoral pulse wave velocity (PWV) and augmentation index were assessed. Serum biochemistry and plasma MMP-9 concentrations were measured and genotyping performed following extraction of genomic DNA. BP, aortic PWV and serum MMP-9 levels were significantly higher in T-allele carriers of the -1562C>T polymorphism with a significant gene-dose effect (P<0.0001). In a stepwise regression model adjusting for known or likely determinants, the 1562C>T polymorphism emerged as an independent predictor of systolic BP (R(2)=0.25, P<0.0001), diastolic BP (R(2)=0.16, P<0.0001) and PWV (R(2)=0.47,P<0.0001). This is the first study to show the effect of MMP-9 polymorphism on BP and aortic stiffness in a hypertensive population. These results suggest that hypertensive patients carrying the T allele may be at increased risk of cardiovascular events.

An evaluation of the effects of renal artery stenting in renovascular hypertension.

Renal artery stenosis is a common cause (1-6%) of secondary hypertension. Renal artery stenting has recently been employed as an adjunct to antihypertensive medication. We evaluated 92 patients who underwent renal angiography of whom 30 were stented. There was a reduction (p < 0.01) in blood pressure immediately post renal artery stenting--systolic BP from 157 +/- 20 to 140 +/- 21 mmHg and diastolic BP from 81 +/- 13 to 72 +/- 12 mmHg was sustained at 6 months follow up (148 +/- 20/76 +/- 12 mmHg) in the outpatients' clinic. The amount of antihypertensive medication did not differ post stenting--2.7 +/- 1.2 pre vs 2.7 +/- 1.2 drugs post procedure. Renal artery stenting did not provide a 'cure' for any patient with atherosclerotic renovascular hypertension and until the results of randomized studies are known we believe use should be restricted.

Impact of Helicobacter pylori on the management of dyspepsia in primary care.

BACKGROUND: It is unclear what impact Helicobacter pylori infection has had on the management of dyspepsia in primary care and to what extent published guidelines on H. pylori are implemented in routine clinical practice. AIM: To assess the impact of H. pylori infection on the management of dyspepsia in primary care. METHODS: Patients referred by primary care doctors to an open-access 13-carbon urea breath test service over a 2-year period for their first urea breath test were included in the study. Individual breath results were linked with data on prescribing obtained from the General Medical Services prescription database. RESULTS: Of 805 patients, 374 (47%) had a positive urea breath test and 431 (54%) a negative urea breath test. Of positive urea breath test patients, only 245 (64%) were prescribed eradication therapy in the 3 months after the breath test and only 43% were referred back for re-testing. In the year after the urea breath test, there was a significant fall in prescribing of antisecretory therapy which was greatest in the patients who received H. pylori therapy (P < 0.001). CONCLUSIONS: There appears to be under and inappropriate treatment of H. pylori infection in primary care, and a low rate of re-testing after eradication, indicating that current guidelines are not well implemented in practice.

The population mortality benefits of maximizing the number of eligible patients receiving appropriate cardiology treatments in Ireland.

BACKGROUND: Coronary heart disease (CHD) mortality rates have been decreasing in many industrialized countries since the 1980s. Up to half this decrease can be attributed to evidence-based medical and surgical cardiology interventions. However, recent studies suggest that modern cardiology treatment uptake levels remain disappointingly low in many patient categories. AIM: To determine the potential for further reductions in CHD mortality in Ireland from increasing the number of eligible patients receiving cardiology treatments. METHODS: A previously validated, cell-based IMPACT CHD mortality model was used to integrate large amounts of data describing CHD patient numbers, and the effectiveness and uptake levels of specific medical and surgical treatments. The CHD mortality reductions potentially achievable through the increased use of specific treatments were then calculated, stratified by age and gender and tested using sensitivity analyses. RESULTS: In 2000, medical and surgical coronary disease treatments together prevented or postponed approximately 1950 CHD deaths in the adult population aged 25-84. However, increasing treatment levels to reach 80% of eligible patients might have prevented or postponed a further 2280 CHD deaths in 2000 (minimum estimate 860, maximum estimate 4000). The biggest gain was from maximizing the treatment uptake of eligible heart failure patients, followed by those receiving statins and secondary prevention therapies. DISCUSSION: Many eligible patients are currently not receiving appropriate evidence-based treatments that would reduce CHD mortality and morbidity. Our results suggest that increasing cardiology treatment uptake in Ireland could at least double the current therapeutic reduction in CHD mortality.

Collagen type-I degradation is related to arterial stiffness in hypertensive and normotensive subjects.

Although arterial stiffness is an independent cardiovascular risk factor associated with both aging and hypertension, relatively little is known regarding the structural changes in the vessel wall that occur with vessel stiffening. We determined if collagen type-I metabolism is related to arterial stiffening in both hypertensive and normotensive subjects. Arterial stiffness was assessed by aortic pulse wave velocity (PWV) and augmentation index (AIx) in 46 subjects (48.7 +/- 2 years, 32 hypertensives) and related to circulating markers of collagen type-I turnover. Collagen synthesis was assessed by the measurement of carboxy-terminal peptide of procollagen type-I (PIP) and collagen degradation by the measurement of carboxy-terminal telopeptide of collagen type-I (ICTP), by quantitative immunoassay. Matrix metalloproteinase-1 (MMP-1) and the tissue inhibitor of metalloproteinase-1 (TIMP-1) were also quantified by immunoassay. The ratio of collagen type-I synthesis to degradation was negatively correlated with both PWV (P<0.05) and AIx (P<0.05), whereas plasma MMP-1 levels displayed a positive correlation with both PWV (P<0.01) and AIx (P<0.01), after adjustment for age and mean arterial pressure. The relationship between collagen type-I turnover and arterial stiffness was similar in both the normotensive and hypertensive subjects. Although circulating markers of collagen synthesis were increased in the hypertensive subjects, this was not related to arterial stiffness. Collagen type-I degradation is increased in relation to collagen type-I synthesis in subjects with stiffer arteries. Matrix metalloproteinase-1, the enzyme responsible for collagen type-I degradation, is positively related to both large elastic and muscular artery stiffness in normotensive and hypertensive subjects.

Acute haemodynamic effects of cigarette smoking in healthy young subjects.

BACKGROUND: Invasive studies in middle-aged patients suggest an acute adverse haemodynamic effect of smoking. AIMS: To study acute changes in blood pressure (BP), cardiac output, peripheral resistance and aortic compliance following cigarette smoking in healthy young subjects. METHODS: Using a non-invasive photoplethysmographic technique we compared the effects of smoking one cigarette with sham smoking in 12 healthy volunteers (22-25 years). Data was analysed using JMP version 5.0. RESULTS: In contrast to sham smoking there was a prompt increase in blood pressure with a maximum effect at 15 min (123 +/- 7/75 +/- 5 to 143 +/- 6/86 +/- 6 mmHg, mean +/- SEM, p < 0.01) which is attributed to a rise in cardiac output (p < 0.05) rather than changes in peripheral vascular resistance. There was also a significant (p < 0.05) increase in heart rate and a reduction in aortic compliance. CONCLUSION: These results suggest that healthor young age do not protect from the adverse effects of smoking.

Regional variation in prescribing for chronic conditions among an elderly population using a pharmacy claims database.

BACKGROUND: Age, gender and geographical regions are recognised factors in inequalities in prescribing for chronic diseases in the elderly. AIM: To compare the health board regional distribution of chronic disease among the elderly and to examine variation in quality prescribing across age, gender and regions. METHODS: Population based study of prescribing for chronic disease using a national pharmacy claims database. All individuals aged 70 years and over (n = 271,518) were eligible. RESULTS: Over 60% of the elderly in all regions received cardiovascular related medication. The South Eastern, North Western and Western Health Boards had below average prescribing for many chronic conditions. Logistic regression identified age, gender and regional variations in prescribing of preventative therapies for CVD and diabetes. CONCLUSION: There is a high prevalence of prescribing for chronic conditions in the elderly in Ireland, and there is evidence of gender, age and residing health board inequalities in prescribing.

Adherence to clinical guidance in the prescribing of oral antithrombotic medication in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation is the commonest cardiac rhythm disturbance and is an independent risk factor for stroke; however, use of oral antithrombotic therapy is reported to be suboptimal in clinical practice. AIM: The aim of the study was to evaluate the prescribing rates of oral antithrombotic therapy in patients with atrial fibrillation to determine if prescribing patterns reflected published clinical guidance. METHOD: Patients with atrial fibrillation, admitted to hospital over a 12-week period were identified and their antithrombotic therapy regimen was analysed using statistical methods. RESULTS: Although 87/100 patients identified were prescribed OAT, the regimen was suboptimal in 35 patients. Patients aged 75 years and older were more likelyto be receiving suboptimal oral antithrombotic treatment compared with younger patients CONCLUSIONS: The benefits and suitability of oral antithrombotic therapy for patients of all ages need to be more comprehensively communicated to prescribers.

Prescribing for patients with diabetes in the community drug schemes.

The aim of the study was to examine the management of diabetes patients particularly in relation to secondary preventative therapies within the community drug schemes across the health board regions in Ireland. The study population was identified using two national primary care prescribing databases from the Long Term Illness (LTI) and General Medical Services (GMS) scheme for 2003. 65,593 patients were identified as having 'treated' diabetes. Logistic regression was used to predict the likelihood of receiving secondary preventative therapies by region and drug scheme using adjusted odds ratios (ORs) and 95% confidence intervals (CI). The proportion of diabetes patients in each drug scheme with Ischaemic Heart Disease (IHD) was also calculated. Prevalence of 'treated' diabetes was calculated for each health board also. Regional and scheme-based variations within each region exist in the prescribing of secondary preventative therapies after adjustment for IHD rates. Prevalence of treated diabetes varied between regions from 1.5% in the Eastern region to 2.2% in the Southern region. While the location of specialised diabetes clinics may be a contributing factor, inequalities in prescribing across regions within the drug schemes are apparent.

Enzyme induction and inhibition.

The rate and extent of drug metabolism significantly influences drug effect. Enzyme induction by increasing the metabolism of drugs may result in important drug interactions. Other implications of enzyme induction include alterations in the metabolism of endogenous substrates, vitamins and activity of extrahepatic enzyme systems. Similarly a wide range of drugs may produce clinically significant drug interactions following enzyme inhibition. Assessment of enzyme induction and inhibition in man involves diverse methods including the use of model drugs.

Changes in prevalence of and prescribing for ischaemic heart disease in Ireland 1990-2002.

BACKGROUND: Secondary prevention therapies, such as angiotension converting enzyme (ACE) inhibitors, beta-blockers and statins, are known to reduce cardiovascular morbidity and mortality. OBJECTIVE: The aim of the study was to examine the prevalence of coronary heart disease (CHD) and the prescribing of secondary preventive therapies in the period 1990-2002. METHODS: The General Medical Services prescription database was used to identify the study cohort, those with CHD, in each year 1990-2002. CHD was defined in two ways: prescription of any nitrate, and co-prescription of nitrate and aspirin. In addition, co-prescription of secondary preventive agents including statins, ACE inhibitors and beta blockers were examined. RESULTS: We found a significant increasing prevalence of CHD from 1990 to 2002 in both men and women. There was a significant increase (p < 0.0001) in the prescribing rate for beta blockers, ACE inhibitors, and for statins, buta significant decrease (p < 0.0001) for calcium channel blockers. CONCLUSION: These trends reflect the growing evidence base on the effectiveness of secondary preventive therapies, and the implementation of the National Cardiovascular Health Strategy.

Propranolol dosage in thyrotoxicosis.

Eighteen thyrotoxic patients receiving chronic treatment with propranolol (160 mg/day) were studied to determine the relationship between plasma propranolol concentration and drug effect. There was a considerable interindividual variability in both the plasma propranolol steady state concentration and the degree of beta-adrenergic blockade. The plasma propranolol steady state concentration correlated significantly with both beta-adrenergic blockage and weight change but not with the degree of subjective improvement. In a group of 40 patients, including 10 severely thyrotoxic patients, who had the dosage of propranolol titrated objectively preoperatively to bring about a greater than 25% reduction in exercise heart rate at the end of a dosage interval, no case of thyroid storm was encountered. Many patients, the younger and severely thyrotoxic in particular, require doses in excess of 160 mg/day to achieve this degree of beta-adrenergic blockade.

Growth in use of statins after trials is not targeted to most appropriate patients.

OBJECTIVE: To determine whether growth in the use of lipid-lowering drugs after publication of studies in the primary and secondary prevention of coronary heart disease is in the population in which benefit was established, particularly middle-aged men. METHODS: We performed a series of pharmacoepidemiologic surveys of community prescribing in Ireland over 4 years. RESULTS: Nationally, the use of lipid-lowering drugs (92% statins) increased approximately fourfold from 1994 to 1998. In the Eastern Health Board region, the number of monthly recipients increased from 447 in April 1994 to 3530 in March 1998. Although use increased steadily after publication of Scandinavian Simvastatin Survival Study (4S) and West of Scotland Coronary Prevention Study (WOSCOPS) in 1994 and 1995, respectively, this occurred to a greater extent in women. However, after the Cholesterol and Recurrent Events (CARE) study in 1996 and subsequent recommendations that targeted statin use, particularly in men from 35 to 69 years old, there was a relatively greater increase in that population but, at 2.3%, it was well short of the target population of 5.8%. More women than men older than 65 years are receiving statins. The 10-mg dosage (a fourth or half that used in studies) is the most frequently dispensed. CONCLUSION: The use of statins, although rising rapidly, is below targets and was initially not directed at the population likely to benefit most or in the recommended dosage. Consequently, the benefits projected from clinical trials may not be seen in clinical practice.

Effect on apparent liver blood flow of histamine-receptor blockers and inhibition of prostaglandin synthesis.

We have recently shown that histamine H2-receptor blockade with cimetidine reduces apparent liver blood flow. To determine the effects of inhibition of prostaglandin synthesis and of H1-receptor blockade and of their additive effects when combined with cimetidine (600 mg), we estimated liver blood flow from the clearance of a single dose (0.5 mg/kg) of indocyanine green (ICG) in six healthy subjects after indomethacin (50 mg. three times during 24 hr) and chlorpheniramine (8 mg. three times during 24 hr). Indomethacin and chlorpheniramine reduced ICG estimated liver blood flow by 18 +/- 3% and 13 +/- 4% (mean +/- SEM). When cimetidine was added to indomethacin or chlorpheniramine, the reductions in flow of 22 +/- 6% and 19 +/- 5% were not significantly greater than that after indomethacin, chlorpheniramine, or cimetidine alone (16 +/- 6%). These data suggest that both histamine acting through H1- and H2-receptors and prostaglandins may influence liver blood flow in man and are consistent with evidence from animal experiments that suggest a role for prostaglandins in H2-mediated vascular responses.

Propranolol dynamics in thyrotoxicosis.

Twenty-five thyrotoxic patients were treated with propranolol (160 mg/day) for 1 to 2 wk. Although the response to therapy varied there was a reduction (p less than 0.001) in supine and exercise heart rates and in sitting pulse rate. Serum triiodothyronine (T3) fell (p less than 0.001) and serum thyroxine did not change during propranolol therapy. Plasma propranolol levels before assessment varied from 5 to 121 ng/ml, and there were positive correlations between them and percentage reduction in exercise (r = 0.78, p less than 0.001) and resting (r = 0.61, n = 14, p less than 0.05) heart rates, percentage reduction in sitting pulse rate (r = 0.73, p less than 0.001), and the percentage reduction in serum T3 (r = 0.59, n = 23, p less than 0.01). Although weight loss ceased in the group as a whole the degree of continued weight loss or weight gain in individual patients was also related to plasma propranolol concentration (r = 0.61, p less than 0.01). The plasma propranolol level correlated (r = 0.62, p less than 0.01) with thyrotoxicosis therapeutic index. There was no correlation between degress of subjective improvement and plasma propranolol level.

Calcium channel blocker drugs and diabetic control.

Calcium channel blockers are now widely used and there have been case reports of hyperglycemia with nifedipine. In a double-blind, randomized, crossover study of the effects of 4 weeks of therapy, each with two dihydropyridine calcium channel blocker drugs, nifedipine and nicardipine, glucose tolerance, plasma insulin levels, and hemoglobin A1 were assessed in 20 patients with non-insulin-dependent diabetes (mean age 59 years). There was no significant difference in glucose tolerance on active therapy (AUC: control, 548.3 +/- 24.8; nifedipine, 559.3 +/- 41.0; and nicardipine, 589.3 +/- 40.3). Similarly, despite producing significant hemodynamic effects, these drugs produced no significant effect on plasma insulin and hemoglobin A1 levels. Calcium channel blocker drugs may be useful alternatives to thiazide diuretics and beta-blockers in the treatment of ischemic heart disease and hypertension, especially in patients with diabetes.

Effect of thyrotoxicosis on liver blood flow and propranolol disposition after long-term dosing.

The effects of thyrotoxicosis on Liver blood flow and propranolol disposition were followed in five patients while thyrotoxic and when euthyroid. Propranolol was taken orally to achieve steady state and then radiolabeled drug was given simultaneously by intravenous injection. Thyrotoxicosis was associated with doubling of both oral and systemic clearances of unbound propranolol, which resulted in an approximately 50% reduction in blood concentrations after oral doses. These changes were attributable to increases in hepatic blood flow and drug-metabolizing activity of the liver. The propranolol elimination t 1/2 was not affected by thyrotoxicosis since the enhanced clearance was offset by a change in volume of distribution. These findings may explain the reduction of plasma propranolol concentration and many of the therapeutic failures reported in the treatment of thyrotoxicosis. The dose required to achieve therapeutic blood concentrations of propranolol in thyrotoxic patients is variable and will usually be substantially larger than that required for euthyroid patients.