Giulia Renda

Awake Systolic Blood Pressure Variability Correlates With Target-Organ Damage in Hypertensive Subjects

Growing evidence associates blood pressure (BP) variability with cardiovascular events in hypertensive patients. Here we tested the existence of a relationship between awake BP variability and target-organ damage in subjects referred for suspected hypertension. Systolic and diastolic BP variability were assessed as the standard deviation of the mean out of 24-hour, awake and asleep BP recordings in 180 untreated subjects, referred for suspected hypertension. Measurements were done at 15-minute intervals during daytime and 30-minute intervals during nighttime. Left ventricular mass index (by echo), intima-media thickness (by carotid ultrasonography), and microalbuminuria were assessed as indices of cardiac, vascular and renal damage, respectively. Intima-media thickness and left ventricular mass index progressively increased across tertiles of awake systolic BP variability (P for trend=0.001 and 0.003, respectively). Conversely, microalbuminuria was similar in the 3 tertiles (P=NS). Multivariable analysis identified age (P=0.0001), awake systolic BP (P=0.001), awake systolic BP variability (P=0.015) and diastolic BP load (P=0.01) as independent predictors of intima-media thickness; age (P=0.0001), male sex (P=0.012), awake systolic (P=0.0001) and diastolic BP (P=0.035), and awake systolic BP variability (P=0.028) as independent predictors of left ventricular mass index; awake systolic BP variability (P=0.01) and diastolic BP load (P=0.01) as independent predictors of microalbuminuria. Therefore, awake systolic BP variability by non-invasive ambulatory BP monitoring correlates with sub-clinical target-organ damage, independent of mean BP levels. Such relationship, found in subjects referred for recently suspected hypertension, likely appears early in the natural history of hypertension.

Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in patients with osteoarthritis and ischemic heart disease.

We performed a placebo‐controlled, randomized study to address whether celecoxib or ibuprofen undermines the functional range of inhibition of platelet cyclooxygenase (COX)–1 activity by aspirin in patients with osteoarthritis and stable ischemic heart disease.

Low-Dose Naproxen Interferes With the Antiplatelet Effects of Aspirin in Healthy Subjects: Recommendations to Minimize the Functional Consequences

OBJECTIVE To investigate whether low-dose naproxen sodium (220 mg twice a day) interferes with aspirins antiplatelet effect in healthy subjects. METHODS We performed a crossover, open-label study in 9 healthy volunteers. They received for 6 days 3 different treatments separated by 14 days of washout: 1) naproxen 2 hours before aspirin, 2) aspirin 2 hours before naproxen, and 3) aspirin alone. The primary end point was the assessment of serum thromboxane B(2) (TXB(2)) 24 hours after the administration of naproxen 2 hours before aspirin on day 6 of treatment. In 5 volunteers, the rate of recovery of TXB(2) generation (up to 72 hours after drug discontinuation) was assessed in serum and in platelet-rich plasma stimulated with arachidonic acid (AA) or collagen. RESULTS Twenty-four hours after the last dosing on day 6 in volunteers receiving aspirin alone or aspirin before naproxen, serum TXB(2) was almost completely inhibited (median [range] 99.1% [97.4-99.4%] and 99.1% [98.0-99.7%], respectively). Naproxen given before aspirin caused a slightly lower inhibition of serum TXB(2) (median [range] 98.0% [90.6-99.4%]) than aspirin alone (P = 0.0007) or aspirin before naproxen (P = 0.0045). All treatments produced a maximal inhibition of AA-induced platelet aggregation. At 24 hours, compared with baseline, collagen-induced platelet aggregation was still inhibited by aspirin alone (P = 0.0003), but not by aspirin given 2 hours before or after naproxen. Compared with administration of aspirin alone, the sequential administration of naproxen and aspirin caused a significant parallel upward shift of the regression lines describing the recovery of platelet TXB(2). CONCLUSION Sequential administration of 220 mg naproxen twice a day and low-dose aspirin interferes with the irreversible inhibition of platelet cyclooxygenase 1 afforded by aspirin. The interaction was smaller when giving naproxen 2 hours after aspirin. The clinical consequences of these 2 schedules of administration of aspirin with naproxen remain to be studied in randomized clinical trials.

Effects of nimesulide on constitutive and inducible prostanoid biosynthesis in human beings

The aim of this study was to test the hypothesis that nimesulide, a nonsteroidal antiinflammatory drug, or its principal metabolite 4‐hydroxynimesulide, is a selective inhibitor of prostaglandin H synthase‐2 in human beings.

Optimal Duration of Antiplatelet Therapy in Recipients of Coronary Drug-Eluting Stents

Four weeks’ therapy with clopidogrel, in addition to aspirin (acetylsalicylic acid), is currently standard care after percutaneous coronary intervention (PCI) with stent implantation. The recent availability of drug-eluting stents (DES), which dramatically reduce restenosis at the site of PCI, has again raised the issue of stent thrombosis. In clinical trials, the risk of stent thrombosis appeared unrelated to the presence of the drug eluting from the stent and was documented within the usual range of ≤1% at 9 months after DES implantation. However, these devices feature delayed strut endothelialisation and there are reports describing late DES thrombosis up to 18 months after PCI, in most cases after clopidogrel has been discontinued.Although infrequent after bare-metal stenting (0.4–2.8%), stent thrombosis is a catastrophic event. Before DES availability, adjunctive intravascular brachytherapy significantly reduced in-stent neointimal proliferation, at the price of a higher-than-expected rate of late stent occlusion (6–8%). In such setting, a 12-month aspirin plus clopidogrel regimen showed a beneficial effect on long-term adverse events.An additional consideration is that, among patients undergoing bare-metal stent PCI, combined antithrombotic therapy with aspirin and clopidogrel has been recently associated with favourable effects on cardiovascular outcome beyond stent thrombosis in two large-scale clinical trials. Therefore, we propose that prolonged combination therapy with aspirin and clopidogrel be mandatory up to 1 year after PCI in all patients receiving DES.

Genetic determinants of blood pressure responses to caffeine drinking

BACKGROUND The widely observed between-subject variability in cardiovascular responses to coffee may have a genetic basis. OBJECTIVE We evaluated acute blood pressure (BP) responses to caffeine and explored whether they are influenced by candidate gene variants affecting caffeine metabolism (for cytochrome P450 1A2), adenosine metabolism (for adenosine receptor and AMP deaminase), or catecholamine receptors. METHODS We recruited 110 healthy male habitual moderate coffee drinkers who refrained from drinking coffee on the day preceding the study. Each subject underwent ambulatory BP monitoring at 6-min intervals for 2 h. Each participant was administered, in a double-blind design, 40 mL of either a decaffeinated coffee preparation plus 3 mg caffeine/kg (caf) or the corresponding vehicle (decaf). The protocol was repeated 24 h later with the alternative preparation. Blood samples were collected for genetic and plasma caffeine and catecholamine evaluations. RESULTS Compared with decaf, caf was associated with a mean (± SD) significant increase in systolic BP of 4 ± 12 mm Hg and in diastolic BP of 3 ± 10 mm Hg (P < 0.001 for both). Plasma caffeine and adrenaline increased after caf, but not after decaf. Of 11 gene polymorphisms analyzed, a relation was observed between the ADORA2A TT variant and the change in SBP peak and between the ADRA2B I variant and the changes in both SBP mean and peak; mean peak change in SBP; these variants were associated with increased SBP responses to caf. CONCLUSIONS Variability in the acute BP response to coffee may be partly explained by genetic polymorphisms of the adenosine A2A receptors and α(2)-adrenergic receptors. This trial is registered at clinicaltrials.gov as NCT01330680.

Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W

AIMS To assess the risk of death after the occurrence of different types of non-fatal events in patients with atrial fibrillation (AF). Antithrombotic therapies in AF have primarily focused on stroke prevention and bleeding. However, strokes and bleeds differ in severity, and the level of severity may differently impact mortality. METHODS AND RESULTS We analysed the risk of subsequent mortality after the occurrence of non-fatal vascular and bleeding events in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE)-W trial. In the 3371 patients randomized to vitamin K antagonists and the 3335 patients randomized to clopidogrel plus aspirin in ACTIVE-W, the hazard ratio (HR) and 95% confidence intervals (95% CIs) for subsequent death associated with the occurrence of non-fatal stroke was 5.58 (95% CI 3.84-8.10, P < 0.0001). Both ischaemic (HR 5.29, 95% CI 3.53-7.93, P < 0.0001) and haemorrhagic strokes (HR 7.38, 95% CI 2.74-19.9, P < 0.0001) increased mortality, but transient ischaemic attacks did not. Disabling strokes (Rankins score > or =3) increased mortality (HR 9.54; 95% CI 6.42-14.2, P< 0.0001), but non-disabling strokes did not. Severe bleeding increased mortality (HR 3.35, 95% CI 2.12-5.27, P < 0.0001), but major bleeding that was not severe according to the study definitions did not. CONCLUSION Non-fatal strokes increased mortality in ACTIVE-W, but non-disabling strokes did not. Among major bleeding events, only those also classified as severe increased mortality. Future research should emphasize the prevention of disabling strokes and severe bleeds and place less emphasis on non-disabling stroke or major bleeds that are not severe.

Platelet function and long-term antiplatelet therapy in women: is there a gender-specificity? A ‘state-of-the-art’ paper

Although the female gender is generally less represented in cardiovascular studies, observational and randomized investigations suggest that-compared with men-women may obtain different benefits from antiplatelet therapy. Multiple factors, including hormonal mechanisms and differences in platelet biology, might contribute to such apparent gender peculiarities. The thrombotic and bleeding risks, as well as outcomes after a cardiovascular event, appear to differ between genders, partly in relation to differences in age, comorbidities and body size. Equally, the benefits of antiplatelet therapy may differ in women compared with men in different vascular beds, during primary or secondary prevention and according to the type of an antiplatelet agent used. This document is an attempt to bring together current evidence, clinical practices and gaps of knowledge on gender-specific platelet function and antiplatelet therapy. On the basis of the available data, we provide suggestions on current indications of antiplatelet therapy for cardiovascular prevention in women with different clinical features; no strong recommendation may be given because the available data derive from observational studies or post hoc/subgroup analyses of randomized studies without systematic adjustments for baseline risk profiles.

Increased short-term blood pressure variability is associated with early left ventricular systolic dysfunction in newly diagnosed untreated hypertensive patients

Background and aim: Twenty-four-hour blood pressure (BP) variability, by ambulatory BP monitoring (ABPM), has been related to left ventricular hypertrophy, independent of mean BP values. We tested the hypothesis that short-term BP variability (BPV) is also related to subclinical left ventricular systolic dysfunction. Methods: We assessed 24-h SBP and DBP variabilities, quantified as standard deviation (SD) of daytime (awake) BP values and as weighted SD of 24-h BP (24-h-weighted BPV), in 309 recently (<6 months) diagnosed, prospectively recruited, and untreated hypertensive patients. Patients were included only if with normal (≥55%) left ventricular ejection fraction (LVEF). Left ventricular systolic function was assessed by echocardiography measuring midwall fractional shortening (MFS), circumferential end-systolic stress (cESS), MFS/cESS, peak systolic wall stress, left ventricular fractional shortening (LVFS), and LVEF. Results: At multivariate analysis, awake and 24-h-weighted SBP variabilities (directly, P = 0.038 and P = 0.002, respectively) as well as relative wall thickness (RWT) (inversely, P = 0.001) were significantly related to cESS. Awake and 24-h SBP average values (inversely, P = 0.011 and P = 0.002, respectively), awake and 24-h-weighted SBP variabilities (inversely, P = 0.017 and P = 0.024, respectively), and RWT (directly, P = 0.001) were all significantly related to MFS/cESS. Finally, awake and 24-h average SBP (directly, P = 0.01 for both), awake and 24-h-weighted SBP variability (directly, P = 0.001 and P = 0.032, respectively), and RWT (inversely, P = 0.001) were all significantly and independently related to peak systolic wall stress. Conclusion: In newly diagnosed never-treated hypertensive patients, in the absence of LVEF changes and independent of left ventricular mass index, higher awake, or 24-h-weighted short-term SBP variabilities are associated with early depressed left ventricular systolic function.

Frequent and possibly inappropriate use of combination therapy with an oral anticoagulant and antiplatelet agents in patients with atrial fibrillation in Europe

Purpose Combined oral anticoagulant (OAC) and antiplatelet (AP) therapy is generally discouraged in atrial fibrillation (AF) outside of acute coronary syndromes or stenting because of increased bleeding. We evaluated its frequency and possible reasons in a contemporary European AF population. Methods The PREvention oF thromboembolic events–European Registry in Atrial Fibrillation (PREFER in AF) prospectively enrolled AF patients in France, Germany, Austria, Switzerland, Italy, Spain and the UK from January 2012 to January 2013. We evaluated patterns of combined VKA-AP therapy in this population. Results Out of 7243 patients enrolled, 5170 (71.4%) were treated with OAC alone, 808 (11.2%) with AP alone and 791 (10.9%) with a combination of OAC and one (dual) or two AP (triple combination therapy). Compared with patients only prescribed OAC, patients on combination treatment had similar Body Mass Index, but more frequently diabetes (p<0.05), dyslipidaemia (p<0.01), coronary heart disease (54.2 vs 18.6%; p<0.01) or peripheral arterial disease (10.2 vs 3.7%; p<0.01). Accordingly, they had a higher mean CHA2DS2VASc (3.7 vs 3.4), and HAS-BLED (2.7 vs 1.9) scores (for both, p<0.01). Of the 660 patients on dual AP+OAC combination therapy, 629 (95.3%) did not have an accepted indication. Out of the 105 patients receiving triple combination therapy, 67 (63.8%) did not have an accepted indication. Conclusions The combined use of OAC and AP therapy is not uncommon in AF, largely inappropriate, explained by the coexistence of coronary or peripheral arterial disease, and not influenced by considerations on the risk of bleeding.