Potentially inappropriate prescribing and cost outcomes for older people: a national population study.

AIMS: Optimization of drug prescribing in older populations is a priority due to the significant clinical and economic costs of drug-related illness. This study aimed to: (i) estimate the prevalence of potentially inappropriate prescribing (PIP) in a national Irish older population using European specific explicit prescribing criteria; (ii) investigate the association between PIP, number of drug classes, gender and age and; (iii) establish the total cost of PIP. METHODS: This was a retrospective national population study (n= 338 801) using the Health Service Executive Primary Care Reimbursement Service (HSE-PCRS) pharmacy claims database. The HSE-PCRS uses the WHO Anatomical Therapeutic Chemical (ATC) classification system and details of every drug dispensed and claimants' demographic data are available. Thirty PIP indicators (STOPP) were applied to prescription claims for those >or=70 years in Ireland in 2007. STOPP is a physiological system based screening tool of older persons' potentially inappropriate prescriptions assessing drug-drug and drug-disease interactions, dose and duration. RESULTS: In our study population PIP prevalence was 36% (121 454 claimants). The main contributors to this were: 56 560 (17%) prescribed proton pump inhibitors at maximum therapeutic dose for >8 weeks, 29 691 (9%) prescribed non-steroidal anti-inflammatories for >3 months, 17 676 (5%) prescribed long-acting benzodiazepines for >1 month and 16 201 (5%) prescribed duplicate drugs. The main determinant of PIP was polypharmacy. The likelihood of PIP increased with a significant linear and quadratic trend (P < 0.0001) with the number of drug classes.The maximum net ingredient cost of PIP was estimated to be euro38 664 640. Total PIP expenditure was estimated to be euro45 631 319, 9% of the overall expenditure on pharmaceuticals in those >or=70 years in 2007. CONCLUSIONS: The findings identify a high prevalence of PIP in Ireland with significant cost consequences.

A competing risks prescription refill model of compliance and persistence.

OBJECTIVES: There is evidence to suggest that noncompliant and nonpersistent behaviors have differing risk factors, clinical consequences, and responses to intervention. This has led to calls for these behaviors to be defined and measured separately to characterize medication-taking behavior comprehensively. Current prescription refill models of compliance are, however, unable to appropriately distinguish between noncompliant and nonpersistent behaviors. To address this limitation, a prescription refill model of medication-taking behavior in which noncompliance and nonpersistence are treated as competing risks is presented. METHODS: The proposed competing risks model of compliance and persistence is compared with a selection of widely applied prescription refill models of compliance and persistence using a common cohort of patients prescribed statin therapy. RESULTS: The competing risks model allows the simultaneous measurement of noncompliance and nonpersistence, the partitioning of their individual contributions to medication-taking behavior, and the estimation of noncompliance risk for patients with varying treatment persistence. The results from this model provide information about the relative and overall contributions of noncompliant and nonpersistent behaviors to medication-taking behavior. The methodology also allows an assessment of the differential influence of various risk factors on these behaviors. CONCLUSIONS: The proposed competing risks model differentiates between noncompliant and nonpersistent behaviors using prescription refill data. Results from the model provide insights into the dynamics of noncompliant and nonpersistent behaviors that have not been possible with current prescription refill methodologies.

Ambulatory arterial stiffness index, pulse wave velocity and augmentation index--interchangeable or mutually exclusive measures?

BACKGROUND: The ambulatory arterial stiffness index (AASI) has been proposed as a novel measure of arterial stiffness and has been prospectively shown to predict stroke and cardiovascular death, but not cardiac death. This index has prompted considerable controversy as to whether it is a true measure of arterial stiffness. OBJECTIVE AND METHODS: The present study aimed to examine three different measures of arterial stiffness - pulse wave velocity (PWV; Complior), wave reflection [augmentation index (AIx)] and AASI - in a large hypertensive population, comparing their determinants and intercorrelations, both unadjusted and adjusted for confounders, and using Bland-Altman analysis to determine 95% confidence intervals for the ability of the AASI to predict PWV, the proposed gold standard of arterial stiffness. RESULTS: The AASI correlated univariately with both PWV and the AIx in individuals overall (r = 0.28 for PWV and r = 0.24 for AIx; both P < 0.001) and in those with untreated or treated hypertension. Adjustment for age in the current study negated entirely the positive correlation between the AASI, PWV and AIx. Additional adjustment for confounders did not significantly alter these nonsignificant relationships. Furthermore, the 95% prediction limits for the AASI to predict PWV were +/- 4.18 m/s and for the AASI to predict AIx were +/- 25.4%, suggesting that the methods would not be interchangeable in a clinical setting. Direct comparative studies would be required to establish the relative predictive strength of each measure and whether combining measures can provide additional risk prediction. Until such data become available, we propose that the measures should not be considered interchangeable.

Beta-blockers reduce aortic stiffness in hypertension but nebivolol, not atenolol, reduces wave reflection.

BACKGROUND: There is conflicting information with regard to the effect of beta-blockers on arterial stiffness and wave reflection. We compared a vasodilating beta-blocker, nebivolol, with atenolol. METHODS: We randomized 40 subjects with untreated hypertension (mean +/- s.e.m. systolic/diastolic blood pressure (BP) of 160 +/- 3/98 +/- 1 mm Hg, age 49 +/- 1 years) 16 of whom were women, to atenolol 50 mg or nebivolol 5 mg daily for 4 weeks. Arterial stiffness was assessed in terms of carotid-femoral pulse wave velocity (PWV, Complior) and arterial wave reflection (augmentation index (AIx) by applanation tonometry, Sphygmocor). RESULTS: Both beta-blockers produced an equal reduction in brachial BP but aortic pulse pressure (PP) was reduced to a greater extent by nebivolol (P < 0.05). PWV was decreased significantly by both therapies (nebivolol: from 11.5 +/- 0.5 to 9.9 +/- 0.5 m/s; atenolol: from 11.1 +/- 0.4 to 9.8 +/- 0.4 m/s; P < 0.01) but only nebivolol significantly reduced AIx (from 35 +/- 5 to 28 +/- 2%, P < 0.05). In addition, whereas PP amplification (PP, mm Hg) decreased with atenolol therapy (from 10 +/- 1 to 7 +/- 1, P < 0.01), it increased with nebivolol therapy (from 8 +/- 1 to 14 +/- 3, P < 0.01). Atenolol reduced heart rate to a greater extent than nebivolol did (14 +/- 3/min reduction by atenolol vs. 8 +/- 2/min reduction by nebivolol, P < 0.05). There was no difference between the two treatments in respect of the effect on transit time. CONCLUSION: The beta-blockers, atenolol and nebivolol, have a similar effect in reducing arterial stiffness in the large elastic aorta, largely secondary to BP reduction. Nebivolol, in contrast to atenolol, has an effect on small muscular arteries, increasing PP amplification and reducing wave reflection, possibly because of increased levels of nitric oxide (NO). Such ancillary properties may impart important distinct hemodynamic effects, and therefore beta-blockers cannot be regarded as a homogeneous group.

History of gestational hypertension is associated with the metabolic syndrome and masked hypertension but not arterial stiffness in women with essential hypertension.

The underlying mechanisms of subsequent increased risk of cardiovascular disease with a history of gestational hypertension (GH) are not known. Untreated hypertensive women (n=155, age 43+/-1 years) underwent ambulatory blood pressure (BP) monitoring and assessment of aortic pulse wave velocity (PWV) and augmentation index (AIx). Despite identical clinic BP readings, the group of women with GH (n=54) had higher (P=.002) ambulatory daytime systolic BP levels and a greater number of extreme nocturnal dippers (P=.005) than the group without GH. Women with GH had higher body mass index (P=.003), greater waist circumference (P=.02), higher levels of triglycerides (P=.002), lower levels of high-density lipoprotein cholesterol (P=.004), a higher prevalence of the metabolic syndrome (P<.05) and microalbuminuria (P=.004), higher plasma renin activity (P=.03), and higher aldosterone levels (P=.01). There was no significant difference in PWV and AIx between the 2 groups. The higher prevalence of the metabolic syndrome, microalbuminuria, masked hypertension, and activation of the renin-angiotensin-aldosterone system but not arterial stiffness may explain the subsequent propensity to high BP and cardiovascular disease in women with GH.

Circadian blood pressure variation: relationship between dipper status and measures of arterial stiffness.

BACKGROUND: Compared with dippers, hypertensive individuals with a nondipping nocturnal blood pressure (BP) profile have more target organ damage and a worse cardiovascular prognosis, potentially mediated through arterial stiffness. OBJECTIVE: To examine arterial stiffness and dipping in a population of 314 untreated hypertensive individuals, mean age 48 +/- 8 years, 55% men. METHODS: Dipping was defined as a 10-20% fall in nocturnal BP; extreme dipping as greater than 20%, nondipping as less than 10%, and reverse-dipping as 0% at most fall in nocturnal BP. Aortic pulse wave velocity (PWV) (Complior) and augmentation index (Sphygmocor) were measured. RESULTS: Groups did not differ by age, gender, 24-h or daytime mean BP, body mass index, smoking, cholesterol, glucose, renin or aldosterone. The relationship between PWV and dipper-status was J-shaped, with extreme-dippers and reverse-dippers having the highest PWV. Nondippers and reverse-dippers had significantly higher age and sex-adjusted PWV compared with dippers. Following multivariate adjustment for age, gender, mean arterial pressure, heart rate and smoking, reverse-dippers had significantly higher PWV than either dippers or nondippers (P = 0.005 and P = 0.006, respectively). Dipper status was not associated with augmentation index. CONCLUSIONS: A reverse-dipper pattern, corresponding to the 95% percentile of the night: day BP ratio on ambulatory BP monitoring, identifies a population group with increased PWV. This difference could not be explained by the measured risk factors. Reverse-dippers had significantly less day: night variability in heart rate and wider pulse pressures at night than any of the other groups, suggesting altered sympathetic tone at night as a potential mechanism.

Comparison of echocardiographic measures of left ventricular diastolic function in early hypertension.

Left ventricular (LV) diastolic dysfunction identifies patients at risk of developing heart failure and may be common in patients with hypertension. The prevalence of LV diastolic dysfunction in patients with newly diagnosed hypertension was compared using criteria provided by the Canadian Consensus, European Study Group, and American Medical Association guidelines. One hundred twenty patients with newly diagnosed untreated hypertension (mean age 46.9 +/- 2.1 years; 62 men, 58 women) with increased blood pressure (clinic >140/90 mm Hg, daytime ambulatory >135/85 mm Hg) underwent comprehensive 2-dimensional echocardiography. Transmitral inflow velocities were measured using pulse-wave Doppler with and without Valsalva's maneuver, and a comprehensive assessment of tissue Doppler velocities was performed. The prevalence of LV diastolic dysfunction varied according to criteria used. There was a high prevalence of LV diastolic dysfunction (59%; n = 71) using Canadian Consensus guidelines; 27% of patients (n = 32) had a pseudonormal pattern unmasked using Valsalva's maneuver and 32% (n = 39) had impaired relaxation at rest. Significantly fewer patients (10%; n = 12) had this diagnosis using European or American Medical Association guidelines (23%; n = 27). Using tissue Doppler imaging (early-late diastolic velocity ratio <1), the prevalence of LV diastolic dysfunction was 59% (n = 71), identical to findings using the Canadian Consensus guidelines. In conclusion, current national consensus guidelines defining LV diastolic dysfunction varied widely and underdiagnosed LV diastolic dysfunction in patients with newly diagnosed hypertension. Tissue Doppler imaging assessment is a rapidly and widely available tool that is as sensitive as the most stringent national guidelines and should be systematically incorporated into a more comprehensive assessment of LV diastolic dysfunction in this population.

Choice of first antihypertensive: simple as ABCD?

BACKGROUND: The AB/CD British Hypertension Society guidelines predict that the blood-pressure response to antihypertensive agents A (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) or B (beta blockers) drugs is better in those aged<55 years, whereas that to agents C (calcium channel blockers) or D (diuretics) agents is better in those aged>or=55 years. METHODS: We conducted a cohort study of 175 consecutive, untreated, hypertensive whites (55% men), aged 19 to 80 years and prospectively randomized to either A/B or C/D antihypertensive agents, and in whom there was no compelling reason to choose a particular drug. Blood pressure (BP) was measured using a semiautomated device (Omron 705CM, Tokyo, Japan) at baseline and 4 weeks after therapy in a single, blind fashion. RESULTS: There was no difference in baseline BP (mean+/-SEM, A/B, 163+/-2/97+/-1 v C/D, 163+/-2/95+/-1 mm Hg). Whereas the A/B drugs were more effective in younger than older patients, expressed as percentage of reduction (13%+/-1%/12%+/-1% v 8.5%+/-1%/7%+/-1%, P<.01), as absolute reduction, or by classification of mean+/-SEM blood pressure into stages of hypertension, the C/D drugs were no more effective than A/B drugs in those aged>55 years. CONCLUSIONS: The arbitrary choice of age 55 years to predict the response to antihypertensive agents in a white population is not supported by our data. A prospective, multicenter study is required to underpin guideline recommendations in relation to using age as a determinant for choice of a particular antihypertensive drug in defined hypertensive populations.

Advanced glycation end-products and arterial stiffness in hypertension.

BACKGROUND: The formation of advanced glycation end-products is associated with arterial stiffness in experimental models and alagebrium (formerly known as ALT-711), an advanced glycation end-product cross-link breaker, has been shown to reduce arterial stiffness in elderly subjects. METHODS: We related plasma concentrations of advanced glycation end-products (AGEs), measured using a noncompetitive immunoassay, and markers of aortic stiffness-pulse wave velocity (PWV) and augmentation index (AIx), a measure of aortic wave reflection-in 46 subjects, aged 47 +/- 2 years, comprising 30 untreated hypertensive and 16 normotensive subjects. Results were analyzed using univariate and multiple logistic regression analysis. RESULTS: Plasma AGEs were significantly higher in hypertensive than in normotensive subjects (7.8 +/- 1 v 3 +/- 1 mug/ml; P < .0001). There was a significant relationship between plasma AGEs and aortic PWV (r = 0.49, P < .01), but not with AIx. In a stepwise regression model age, plasma AGE levels, smoking status, and total cholesterol explained 67% of the variability in PWV. For AIx, the only variables that entered the model were age, gender, and heart rate (R(2) = 0.53, P < .0001) with no contribution from plasma AGEs. CONCLUSIONS: Concentration of plasma AGEs is significantly higher in hypertensive than in normotensive subjects and related to aortic stiffness independent of age and blood pressure, with no relationship with aortic wave reflection. Plasma AGEs may play a blood pressure-independent role in large but not small vessel remodeling in essential hypertension.

Choice of first antihypertensive--are existing guidelines ignored?

AIMS: To determine adherence to hypertension guidelines in relation to age and diabetes. METHODS: The Irish HSE-PCRS prescribing database identified patients initiating antihypertensive monotherapy in 2005. Logistic regression predicted the likelihood of therapy according to guidelines. RESULTS: The odds ratio (OR) of receiving therapies according to the guideline recommendations in those <55 years vs. > or =55 years was 1.31 (95% CI 1.26, 1.37). Diabetics were more likely than nondiabetics to receive antihypertensives other than beta-adrenoceptor blockers (OR 2.97, 95% CI 2.74, 3.21). CONCLUSIONS: Our findings show some adherence to the guidelines in relation to age but selective prescribing of antihypertensives for diabetics.

Explaining the recent decrease in coronary heart disease mortality rates in Ireland, 1985-2000.

STUDY OBJECTIVES: To examine the proportion of the recent decline in coronary heart disease (CHD) deaths in Ireland attributable to (a) "evidence based" medical and surgical treatments, and (b) changes in major cardiovascular risk factors. DESIGN SETTING: IMPACT, a previously validated model, was used to combine and analyse data on the use and effectiveness of specific cardiology treatments and risk factor trends, stratified by age and sex. The main data sources were published trials and meta-analyses, official statistics, clinical audits, and observational studies. RESULTS: Between 1985 and 2000, CHD mortality rates in Ireland fell by 47% in those aged 25-84. Some 43.6% of the observed decrease in mortality was attributed to treatment effects and 48.1% to favourable population risk factor trends; specifically declining smoking prevalence (25.6%), mean cholesterol concentrations (30.2%), and blood pressure levels (6.0%), but offset by increases in adverse population trends related to obesity, diabetes, and inactivity (-13.8%). CONCLUSIONS: The results emphasise the importance of a comprehensive strategy that maximises population coverage of effective treatments, and that actively promotes primary prevention, particularly tobacco control and a cardioprotective diet.

Aldosterone-to-renin ratio, arterial stiffness, and the response to aldosterone antagonism in essential hypertension.

BACKGROUND: Some 10% to 15% of hypertensive patients have hyperaldosteronism, an increased ambulant aldosterone-to-renin ratio. As aldosterone reduces arterial compliance, we examined the relationship between aldosterone-to-renin ratio, aortic blood pressure (BP), arterial stiffness, and the effect of spironolactone in a hypertensive population. METHODS: In 24 untreated patients (mean age 51 +/- 2 years, 10 women), we assessed arterial stiffness by augmentation index-height of the late systolic peak in the aorta, pulse pressure (Sphygmocor), and aortic pulse wave velocity (Complior). RESULTS: There were significant positive correlations between the aldosterone-to-renin ratio and aortic systolic pressure, aortic pulse pressure, and augmentation index and negative correlations with pulse pressure amplification, but none with brachial BP or pulse wave velocity. After randomization in a cross-over design to 50 mg of spironolactone or 2.5 mg of bendroflumetazide for 4 weeks with washout period of 1 month, both drugs significantly reduced brachial BP, but only spironolactone reduced (P < .001) pulse wave velocity and augmentation index, which remained significant when corrected for its greater reduction in mean BP. There were significant (P < .001) positive correlations between the ratio and decrease in aortic systolic (r = 0.78), mean (r = 0.75), diastolic BP (r = 0.66), aortic pulse pressure (r = 0.69, augmentation index (r = 0.64) and with, brachial systolic pressure (r = 0.66), brachial pulse pressure (r = 0.44, P < .05) and pulse pressure amplification (r = 0.46, P < .05). Such relationships were not found with pulse wave velocity. CONCLUSIONS: The aldosterone-to-renin ratio may have an important role in determining arterial stiffness, particularly wave reflection and aortic systolic pressure and is of predictive value for the responsiveness to spironolactone. Aldosterone antagonism has BP-independent effects on arterial stiffness.

Adiponectin and arterial stiffness.

BACKGROUND: Adiponectin, an anti-inflammatory adipocytokine, is reduced in hypertension, diabetes, and coronary artery disease (CAD). Arterial stiffness, as aortic pulse wave velocity (PWV) in hypertension and diabetes, and as augmentation index (AIx) in CAD, is independently associated with cardiovascular mortality. We explored the relationship between adiponectin and arterial stiffness in essential hypertension. METHODS: Seventy-six untreated patients, 34 women, aged 47 +/- 1 years, mean +/- SEM with essential hypertension, had blood pressure (BP), carotid-femoral PWV, AIx plasma adiponectin, and proinflammatory cytokine C-reactive protein (CRP) measured using ELISA technique after an overnight fast. Results were analyzed using univariate and multiple logistic regression analysis. RESULTS: There was a significant positive relationship between log adiponectin and AIx (r = 0.33, P < .005) and plasma HDL-cholesterol (r = 0.40, P < .001). In contrast there were significant negative relationships with PWV (r = -0.24, P < .05), transit time (r = -0.37, P < .001), and pulse pressure amplification (r = -0.30, P < .005) in addition to waist circumference, waist-to-hip ratio, height, and weight. In a stepwise regression model, the independent predictors of AIx were heart rate, height, mean arterial pressure, age, and gender (R2= 0.69, P < .0001) with no contribution from adiponectin. However, for PWV (R2= 0.59, P < .0001) the independent determinants were mean arterial pressure, age, and adiponectin. CONCLUSIONS: These results show a divergent relationship between adiponectin and arterial stiffness, negative for PWV, and positive for wave reflection (AIx). Anthropomorphic factors, particularly height, weight, and heart rate may influence the relationship to the latter. Adiponectin is an independent predictor of aortic PWV but not of AIx.

Does aldosterone-to-renin ratio predict the antihypertensive effect of the aldosterone antagonist spironolactone?

BACKGROUND: The recognition that some 10% to 15% of the hypertensive population may have aldosterone excess has increased the frequency of measurement of the aldosterone-to-renin ratio (ARR) and the use of aldosterone antagonists. Whether this ratio will predict the blood pressure (BP) response to spironolactone is not clear. METHODS: We correlated the BP response to spironolactone 50 mg/day to baseline ARR in 69 hypertensive patients (mean [+/-SD] age 57 +/- 2 years, 65% male), consisting of 39 subjects with long-standing hypertension (4.0 +/- 0.2 years) whose hypertension was uncontrolled on at least three antihypertensive medications and 30 previously untreated patients who were randomized in a cross-over design to receive either spironolactone 50 mg/day or bendroflumethiazide 2.5 mg/day for 4 weeks. RESULTS: After 4 weeks of spironolactone, BP in patients with never-treated hypertension was reduced by 18 +/- 3 / 11 +/- 1 mm Hg. There was a highly significant correlation between log ARR and the fall in systolic BP (r = 0.69, P < .001) and diastolic BP (r = 0.45, P < .05). Nine of ten patients with low renin activity (< or =0.5 ng/mL/h) showed a >20-mm Hg fall in systolic BP. No such correlations were seen when BP was reduced by bendroflumethazide 2.5 mg. For patients with resistant hypertension, despite a BP reduction of 28 +/- 3 / 13 +/- 2 mm Hg after 14 weeks of spironolactone, there was no relationship between the reduction in BP and the ARR; however, subjects with pretreatment potassium <4.0 mmol/L had a greater response than those with levels > or =4.0 mmol/L (34 +/- 3 / 16 +/- 2 v 20 +/- 6 / 8 +/- 3 mm Hg, P < .05) CONCLUSIONS: Based on the study results, ARR and low renin activity may predict the response to spironolactone in never-treated hypertensive patients but not in patients taking antihypertensive drugs, possibly because of the effect of these agents on ARR. In such patients a trial of spironolactone is required to assess the BP response.

Aging is associated with increased matrix metalloproteinase-2 activity in the human aorta.

BACKGROUND: Aging is a major risk factor for the development of arterial stiffness and vascular disease, and it is related to the upregulation of matrix metalloproteinase-2 (MMP-2) in the aorta of rats and nonhuman primates. This study aimed to determine whether MMP activity in the human vasculature changes with aging. We also assessed regional differences in MMP activity at two locations in the arterial tree, the aorta and the internal mammary artery (IMA). METHODS: Both MMP-2 and MMP-9 activity in the human aorta and IMA were determined by gelatin zymography and were localized within the tissue using in situ zymography. Tissue inhibitor of metalloproteinase-2 (TIMP-2) levels was determined by Western blot. RESULTS: Active MMP-2 (but not pro-MMP-2, pro-MMP-9, or active MMP-9) was positively correlated with age in the human aorta (r = 0.65; P < .001) but not in the IMA. Active MMP-2 and TIMP-2 (but not pro-MMP-2 or pro- or active MMP-9) levels are higher in the aorta than in the IMA (P < .001; P < .05). In the aorta, MMP activity is highest in the intima and is also detectable in the media and adventitia. To a lesser extent, MMP activity is present in all layers of the IMA. CONCLUSIONS: This study demonstrates that age-related MMP-2 upregulation occurs in the human aorta but not in the IMA.

Taking blood pressure -- no laughing matter!

BACKGROUND: Humour is used commonly to relax subjects when their blood pressure is being measured. However the short-term effect of laughter on blood pressure is not described. METHODS: Sixteen normotensive volunteers had blood pressure measured using a validated automated oscillometric sphygmomanometric device (Omron 705 CP) as control and during three episodes of laughter while viewing a humorous sit-com video. RESULTS: Blood pressure was stable in the control period. There was a significant rise (P<0.01) in systolic blood pressure from 115 mmHg (108-121, mean 95% confidence interval) to 127 mmHg (120-135) during laughing. The increase in diastolic pressure 71 (67-74) to 73 (69-77) mmHg was not significant. CONCLUSION: Laughing has an acute effect on systolic blood pressure. Patients should not be encouraged to laugh when their blood pressure is being measured.

Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors.

The HMG-CoA reductase inhibitors (statins) are effective in both the primary and secondary prevention of ischaemic heart disease. As a group, these drugs are well tolerated apart from two uncommon but potentially serious adverse effects: elevation of liver enzymes and skeletal muscle abnormalities, which range from benign myalgias to life-threatening rhabdomyolysis. Adverse effects with statins are frequently associated with drug interactions because of their long-term use in older patients who are likely to be exposed to polypharmacy. The recent withdrawal of cerivastatin as a result of deaths from rhabdomyolysis illustrates the clinical importance of such interactions. Drug interactions involving the statins may have either a pharmacodynamic or pharmacokinetic basis, or both. As these drugs are highly extracted by the liver, displacement interactions are of limited importance. The cytochrome P450 (CYP) enzyme system plays an important part in the metabolism of the statins, leading to clinically relevant interactions with other agents, particularly cyclosporin, erythromycin, itraconazole, ketoconazole and HIV protease inhibitors, that are also metabolised by this enzyme system. An additional complicating feature is that individual statins are metabolised to differing degrees, in some cases producing active metabolites. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. Cerivastatin is also metabolised by CYP2C8. Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter present in the small intestine that may influence their oral bioavailability. In clinical practice, the risk of a serious interaction causing myopathy is enhanced when statin metabolism is markedly inhibited. Thus, rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin. Itraconazole has been shown to increase exposure to simvastatin and its active metabolite by at least 10-fold. Pharmacodynamically, there is an increased risk of myopathy when statins are coprescribed with fibrates or nicotinic acid. This occurs relatively infrequently, but is particularly associated with the combination of cerivastatin and gemfibrozil. Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring. Knowledge of the pharmacokinetic properties of the statins should allow the avoidance of the majority of drug interactions. If concurrent therapy with known inhibitors of statin metabolism is necessary, the patient should be monitored for signs and symptoms of myopathy or rhabdomyolysis and the statin should be discontinued if necessary.

Reduction in arterial stiffness with angiotensin II antagonist is comparable with and additive to ACE inhibition.

We measured the effects of angiotensin II blockade on arterial stiffness, augmentation index (AI%), pulse wave velocity (PWV), and blood pressure (BP) in 12 hypertensive patients (mean 49 +/- 11 years) in a 4-week, randomized, cross-over study comparing valsartan 160 mg/day with captopril 100 mg/day, with a 2-week washout period. Subsequently both therapies were combined. Reductions in PWV and AI% remained significant when corrected for BP. Combined therapy reduced PWV and AI% (P < .05) more than monotherapy, even when corrected for BP. The study shows that angiotensin receptor antagonists reduce arterial stiffness in hypertension comparable with and possibly additive to angiotensin converting enzyme inhibition.

Divergent effect of acute and chronic alcohol on arterial stiffness.

To study the effects of alcohol on large artery function we measured arterial wave reflection in the aorta as augmentation index (AI%) by applanation tonometry in 324 subjects (18 to 86 years, 223 male). In eight subjects, when ingested acutely, red wine containing alcohol (0.8 g/kg), but not dealcoholized wine, reduced (P < .01) blood pressure (BP), pulse wave velocity, and AI%. Men with an excessive alcohol consumption (>21 units/week) had a higher AI% (12 +/- 2 v 5 +/- 2, P < .05) and BP, particularly aortic systolic, than did those with a lesser intake. This study suggests that alcohol when ingested acutely may reduce arterial stiffness, although alcohol when ingested chronically, in excess, increases it.

Spurious systolic hypertension of youth: fit young men with elastic arteries.

BACKGROUND: We examined the role of high pulse pressure (PP) amplification in spurious systolic hypertension (SSH). METHODS: We recorded demographic characteristics, brachial blood pressure (BP) (Omron Model HEM-705 CP, Vernon Hills, IL), aortic BP, and arterial wave reflection (Sphygmocor, AtCor Medical, version 6.2, NSW, Australia) and PP amplification in 174 healthy medical students (87 male) and 22 young male hypertensive subjects. RESULTS: Eleven subjects had SSH (147 +/-2 v control 114 +/-1 mm Hg, mean +/- SEM,), normal aortic and brachial diastolic BP with an aortic pressure waveform that was normal in contour and amplitude. All were male, tall, nonsmokers, and active in sports, with slower heart rate, reduced arterial wave reflection (-8 +/- 3 v -0.7 +/-1) and enhanced PP amplification (31 +/-1 v 18 +/-1 mm Hg, P <.01. In contrast, male hypertensive subjects had reduced amplification (14 +/-0.9 mm Hg) and enhanced arterial wave reflection (17 +/-1.9). CONCLUSIONS: The SSH of youth, with raised brachial but normal aortic systolic BP, is commonly seen in tall men who are active in sports and are nonsmokers. It may be explained by the exaggerated first systolic peak in the brachial artery pressure waveform, which is due to very high PP amplification and low arterial wave reflection due to elastic arteries.