A. Tonkin

Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials.

BACKGROUNDnWhether statin therapy is as effective in women as in men is debated, especially for primary prevention. We undertook a meta-analysis of statin trials in the Cholesterol Treatment Trialists (CTT) Collaboration database to compare the effects of statin therapy between women and men.nnnMETHODSnWe performed meta-analyses on data from 22 trials of statin therapy versus control (n=134,537) and five trials of more-intensive versus less-intensive statin therapy (n=39,612). Effects on major vascular events, major coronary events, stroke, coronary revascularisation and mortality were weighted per 1.0 mmol/L reduction in LDL cholesterol and effects in men and women compared with a Cox model that adjusted for non-sex differences. For subgroup analyses, we used 99% CIs to make allowance for the multiplicity of comparisons.nnnFINDINGSn46,675 (27%) of 174,149 randomly assigned participants were women. Allocation to a statin had similar absolute effects on 1 year lipid concentrations in both men and women (LDL cholesterol reduced by about 1.1 mmol/L in statin vs control trials and roughly 0.5 mmol/L for more-intensive vs less-intensive therapy). Women were generally at lower cardiovascular risk than were men in these trials. The proportional reductions per 1.0 mmol/L reduction in LDL cholesterol in major vascular events were similar overall for women (rate ratio [RR] 0.84, 99% CI 0.78-0.91) and men (RR 0.78, 99% CI 0.75-0.81, adjusted p value for heterogeneity by sex=0.33) and also for those women and men at less than 10% predicted 5 year absolute cardiovascular risk (adjusted heterogeneity p=0.11). Likewise, the proportional reductions in major coronary events, coronary revascularisation, and stroke did not differ significantly by sex. No adverse effect on rates of cancer incidence or non-cardiovascular mortality was noted for either sex. These net benefits translated into all-cause mortality reductions with statin therapy for both women (RR 0.91, 99% CI 0.84-0.99) and men (RR 0.90, 99% CI 0.86-0.95; adjusted heterogeneity p=0.43).nnnINTERPRETATIONnIn men and women at an equivalent risk of cardiovascular disease, statin therapy is of similar effectiveness for the prevention of major vascular events.nnnFUNDINGnUK Medical Research Council, British Heart Foundation, Australian National Health and Medical Research Council, European Community Biomed Program.

Lack of effect of fish oil supplementation on blood pressure in treated hypertensives.

Fish and fish oils have been reported to reduce blood pressure in normotensives and untreated hypertensives. The present study examined the effect of dietary supplementation with fish oil on blood pressure in 20 treated hypertensives with controlled blood pressures who continued their usual antihypertensive drug treatment throughout. A double-blind, randomized crossover design was used, with two phases, each of 8 weeks duration. In one phase, subjects took fifteen 1 g fish oil capsules (Lipitac; Reckitt and Colman Pharmaceuticals, Sydney, Australia) daily, and in the other, 15 capsules of identical appearance containing 1 g olive oil daily. There was no difference between the treatment phases for any blood pressure parameter, heart rate or body weight, but blood pressure was lower in both phases compared with pretreatment values. The fasting plasma triglyceride concentration was 30% lower in the fish oil phase (P less than 0.001), but there was no difference between the phases for plasma concentrations of total or high-density lipoprotein (HDL) cholesterol. We conclude that, in treated hypertensives with controlled blood pressures, any additional fall in blood pressure produced by dietary supplementation with fish oil is so small that the requirement for antihypertensive drug therapy is unlikely to be reduced.

Effects of age and isolated systolic hypertension on cardiovascular reflexes

Objectives: Given the reported relationship between systolic hypertension and orthostatic hypotension in the elderly, to test the hypothesis that systolic hypertension causes impairment of the cardiovascular reflex function additional to the effects of age alone. Design Responses were compared in normotensive healthy young (n = 12) and elderly (n = 15) participants and elderly participants with disproportionate supine systolic hypertension (n = 11) using a baroreceptor-mediated stress (head-up tilt) and two non-baroreceptor-mediated stimuli (cold pressor test and isometric exercise). Methods: Blood pressure and heart rate were measured by oscillometry before and during the three stress tests. Forearm blood flow was measured by venous occlusion plethysmography and pulse wave velocity (PWV) by Doppler ultrasound. Results: Percentage changes in systolic/diastolic (SBP/DBP) blood pressure with head-up tilt were 0/+11, −3/0 and −6/+1 mmHg in the young and elderly normotensives and elderly systolic hypertensives, respectively. Both elderly groups had reduced DBP responses to tilt compared with the young (P<0.01). All three groups had similar percentage changes in blood pressure responses to non-baroreflex-mediated stresses (cold pressor test: +10/+23, +11/+11, +10/+15; sustained isometric exercise: +18/+33, +22/+24, +13/+17 in the young and elderly normotensives and elderly systolic hypertensives, respectively). Aorto-iliac PWV adjusted for blood pressure was significantly higher in both elderly groups compared with the young (P<0.01) but there was no difference between elderly normotensives and hypertensives. Unadjusted PWV was higher in elderly hypertensives than in elderly normotensives (P<0.05). Conclusions: Compared with healthy young participants, both elderly groups had similarly attenuated blood pressure responses to tilt and reduced arterial compliance. Systolic hypertension is not associated with additional impairment of cardiovascular reflex function over and above the effects of age. The reported association between supine systolic hypertension and orthostatic hypotension does not appear to be a causative one.

Felodipine, Metoprolol and Their Combination Compared with Placebo in Isolated Systolic Hypertension in the Elderly

This study compared with placebo the efficacy and tolerability of optimised doses of felodipine 5-20 mg daily, metoprolol 50-200 mg daily and their combination in subjects 60 years or over with isolated systolic hypertension. The study employed a randomised double-blind crossover design with allocation of treatment order within subjects by Latin squares. For each subject, after a single-blind run-in placebo phase, there were four randomised treatment phases each of six weeks duration, with a dose titration step at three weeks if necessary. Twenty-eight subjects entered the randomised phases of the study and twenty-one completed all four phases--13 male, 8 female (ages: median 71, range 59-85 years). At the end of both the felodipine and metoprolol phases systolic and diastolic pressure were reduced at 2 hours postdose compared with the placebo phase (p < 0.001), the blood pressure reduction with felodipine (-40/-20 mmHg) being greater than that with metoprolol (-15/-9 mmHg) (p < 0.01). Immediately predose (12 hours postdose) there was a persisting reduction of supine systolic blood pressure (-17 mmHg) with felodipine (p < 0.001), but there was no significant effect of metoprolol. At both measurement times the two drugs when in combination had an additive effect on blood pressure. There was a 20% increase in reported symptoms during each of the active treatment phases. Four subjects withdrew during the randomised phases because of probable drug-related adverse events and six subjects required dosage reductions during the felodipine or combination phases.(ABSTRACT TRUNCATED AT 250 WORDS)

Mono- and Combination Therapy with Felodipine or Enalapril in Elderly Patients with Systolic Hypertension

Using a randomised double-blind crossover design with Latin square allocation of treatments in 20 subjects (7 male, 13 female-ages: 61-87 years) with systolic hypertension, we investigated the efficacy and tolerability of once daily felodipine (extended release) 5-20 mg, enalapril 5-20 mg and their combination compared with placebo in four treatment phases each of 6 weeks duration. During each phase, doses were titrated to achieve a predose clinic supine systolic blood pressure of 140 mmHg or to a predetermined maximum dose. In both the felodipine and combination phases, predose supine and standing systolic and diastolic pressures were significantly reduced compared with the placebo phase (decrease in supine pressure: -13/-5 and -18/-7, respectively). Only predose supine diastolic pressure was significantly reduced (-3 mmHg) compared to placebo in the enalapril phase. In combination the effects of the two drugs on predose blood pressure were additive. There was a 40-60% increase in reported symptoms in the felodipine and combination phases compared with the placebo and enalapril phases. Thus, in elderly subjects with systolic hypertension, felodipine effectively reduces blood pressure throughout the dose interval but with vasodilator adverse effects. In contrast, enalapril is well tolerated but is less effective in reducing blood pressure throughout the whole dose interval.

Diltiazem and atenolol in essential hypertension : additivity of effects on blood pressure and cardiac conduction with combination therapy

In 15 patients with mild to moderate essential hypertension, the effects of diltiazem (120 mg twice daily) were compared with those of atenolol (50 mg once daily), the two drugs in combination, and placebo in a randomized double-blind cross-over study with treatment phases of 4 weeks duration. Blood pressure was reduced in the active treatment phases (supine blood pressure: diltiazem, 172/92 mmHg; atenolol, 172/92 mmHg; diltiazem plus atenolol, 164/88 mmHg; pooled estimate of s.e.m. by analysis of variance = 3/1) compared with placebo (180/101 mmHg). Factorial analysis confirmed fully additive antihypertensive effects of the drugs in combination. The time interval from the beginning of the P wave to the beginning of the QRS complex (P-R interval) was longer during combination therapy (0.184s) compared with either diltiazem (0.175s) or atenolol (0.174s) alone, or placebo (0.164s); s.e.m. by analysis of variance = 0.003. No clinically significant conduction disturbances occurred. Plasma atrial natriuretic peptide was elevated by atenolol but not diltiazem. Thus, in subjects with uncomplicated essential hypertension, diltiazem and atenolol had equal antihypertensive efficacy when used alone, and fully additive effects in combination, on both blood pressure and cardiac conduction.

Effect of Indomethacin on Blood Pressure Control during Treatment with Nitrendipine

This study tested the hypothesis that treatment with a nonsteroidal anti-inflammatory drug will not alter the hypotensive effect of a dihydropyridine calcium channel antagonist. Fifteen essential hypertensives (ages 58-80 years) had a supine diastolic blood pressure (DBP) < 100 mmHg after 4 weeks monotherapy with nitrendipine 5-20 mg twice daily. They entered a double-blind randomised crossover study in which the addition of indomethacin 25 mg three times daily was compared with placebo in treatment phases each of 4 weeks duration. Subjects were seen weekly and measurements in the last 2 weeks of each phase were compared. Supine blood pressure (mean +/- SE) was higher in the indomethacin phase (158 +/- 4/80 +/- 2) than in the placebo phase (154 +/- 4/76 +/- 3) (p < 0.01 for DBP). In 6/15 (40%) of subjects the increase in supine diastolic blood pressure with indomethacin was > 5 mmHg. Plasma urea was also increased in the indomethacin phase: 7.6 +/- 0.6 mmol/l compared with placebo: 6.3 +/- 0.5 mmol/l (p < 0.001). The study has demonstrated that concurrent treatment with the NSAID indomethacin impairs the blood pressure lowering effect of the dihydropyridine calcium channel antagonist nitrendipine. This increase in blood pressure with indomethacin in subjects treated with nitrendipine may represent either an independent pressor effect of indomethacin or a reduced vasodilator prostanoid contribution to the hypotensive effect of nitrendipine. This blood pressure increase may be sufficient to interfere significantly with clinical blood pressure control in some subjects.

Low blood pressure and low energy: (how) are they related?

When discussing this topic, it is vital to be clear about which form of low blood pressure and which form of fatigue are being considered. First, it is clear that acute hypotension accompanying a catastrophic event such as myocardial infarction, severe trauma or septic shock, is a different entity from chronic hypotension. Fatigue is likely to be the least of the problems faced by a patient in one of these situations. Furthermore, the causes, associations and implications of ‘constitutional’ chronic hypotension (usually lifelong, present in both supine and standing positions in otherwise healthy people, often asymptomatic, and associated with longevity) are very different from those of orthostatic hypotension (usually acquired, often associated with supine hypertension, related to autonomic dysfunction and often secondary to disease states such as diabetes or extrapyramidal degenerative disorders which may reduce lifespan). Similarly, the implications of the presence of the isolated symptom, fatigue, or as operationalized by Lucas et al. [1], ‘easy fatiguability’, differ markedly from those of a diagnosis of ‘chronic fatigue syndrome’ (CFS) based on standard diagnostic criteria.

Accuracy of the takeda TM-2420 ambulatory blood pressure monitor

1. The accuracy of blood pressure measurement with the Takeda TM‐2420 ambulatory blood pressure monitor and the TM‐2020 data recorder have been assessed by comparison with simultaneous measurements taken using auscultation and direct femoral artery measurements.

Dispositional factors do not contribute to the enantiospecificity of the cardiovascular effects of phenylpropanolamine

The pharmacokinetics and blood pressure response of the phenylpropanolamine enantiomers (i.e., d‐ and l‐phenylpropanolamine) were determined after the separate oral administration of racemic dl‐phenylpropanolamine (75 mg), l‐phenylpropanolamine (37.5 mg), and d‐phenylpropanolamine (37.5 mg) to six healthy volunteers. No significant differences were observed between any of the pharmacokinetic parameters of d ‐ and l‐phenylpropanolamine when the enantiomers were administered individually or as the racemate. There was also no difference in the ex vivo plasma protein binding of d ‐ and l‐phenylpropanolamine, determined individually or as the racemate. Significant increases from baseline in systolic and diastolic blood pressure (supine and standing) were observed for dl ‐ and l‐phenylpropanolamine, whereas d‐phenylpropanolamine had no effect on blood pressure. The effects of dl‐ and l‐phenylpropanolamine on blood pressure were not significantly different. The data from this study show that pharmacokinetic factors do not contribute to the stereospecificity of the cardiovascular effects of phenylpropanolamine or to the interindividual variability in the blood pressure response to phenylpropanolamine.