Biweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome-encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor-risk diffuse large B-cell lymphoma and moderate to high 'life threat' impact cardiopathy

This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high 'life threat' impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73years, range: 62-82; 37% >75years) at a median interval of 15·6 (range, 13-29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4-year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n=3), therapy discontinuations (no-response n=2; toxicity n=6), relapse (n=6) and death in CR (n=3). Incidence of cardiac grade 3-5 adverse events was 7/41 (17%; 95% confidence interval: 8-31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P=0·007) with patients scoring ≤7 having a longer TTF (66% vs. 29%; P=0·009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF.     

Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis

OBJECTIVES: To compare the effects of angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors on the risk of myocardial infarction, stroke, cardiovascular mortality and total mortality. METHODS: We conducted a meta-analysis of randomized comparative trials between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors. Inclusion criteria were publication in peer-reviewed journals indexed in Medline, randomized comparison of angiotensin II receptor blockers vs. angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers + angiotensin-converting enzyme inhibitors vs. angiotensin-converting enzyme inhibitors, report of major complications including myocardial infarction, stroke, cardiovascular mortality or all-cause mortality; average follow-up of at least 1 year in at least 200 patients. RESULTS: Six trials fulfilled the inclusion criteria, for a total of 49 924 patients. In the pooled estimate, there were no significant differences between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors on the risk of myocardial infarction (odds ratio 1.01; 95% confidence interval 0.95-1.07; P = 0.75), cardiovascular mortality (odds ratio 1.03; 95% confidence interval 0.98-1.08; P = 0.23) and total mortality (odds ratio 1.03; 95% confidence interval 0.97-1.10; P = 0.20). This was the case also when the analysis involved only the comparison between angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Overall, the risk of stroke was slightly lower with angiotensin II receptor blockers than angiotensin-converting enzyme inhibitors (odds ratio 0.92; 95% confidence interval 0.85-0.99; P = 0.037), the direct angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers comparison showing a nonsignificant trend in a similar direction. Statistical heterogeneity among trials was not significant, with a low to null inconsistency statistic, for stroke (P = 0.67), myocardial infarction (P = 0.86), cardiovascular mortality (P = 0.14) and total mortality (P = 0.12). CONCLUSION: This overview suggests that angiotensin II receptor blockers are as effective as angiotensin-converting enzyme inhibitors on the risk of myocardial infarction, cardiovascular mortality and total mortality. Angiotensin II receptor blockers may be slightly more protective than angiotensin-converting enzyme inhibitors on the risk of stroke.     

Native versus primary prosthetic valve endocarditis: comparison of clinical features and long-term outcome in 353 patients

BACKGROUND AND AIM OF THE STUDY: The study aim was to compare preoperative and intraoperative features, and long-term outcome of patients operated on for native (NVE) and primary prosthetic valve endocarditis (PVE). METHODS: Between January 1978 and December 2002, 258 patients (mean age 47.5 +/- 16 years) were referred for NVE, and 95 for PVE. Demographics, clinical preoperative conditions, indications to surgery, microbiological data, surgical pathology, early postoperative course and long-term outcome were compared via hospital chart review and outpatient clinic follow up. RESULTS: Female sex prevailed in the PVE group (49.5%) versus NVE (27.1%; p < 0.0001). Mitral valve involvement was more common in PVE (46.3% versus 24.8%, p = 0.0001), and multivalvular in 16.3% of NVE patients versus 4.2% of PVE (p = 0.001). Active endocarditis (80.6% versus 58.9%, p = 0.00004) and preoperative embolism (29.5% versus 11.6%, p = 0.0002) were significantly prevalent in the NVE group. Emergency operation (21.1% versus 10.5%, p = 0.009) and preoperative NYHA class IV or V (40% versus 19.8%, p < 0.0001) were significantly more frequent in PVE. Overall hospital mortality was 11.3% (n = 40), with 6.6% among NVE patients and 24.2% among PVE (p < 0.0001). Mean follow up (94% complete) was 5.8 +/- 5.3 years (6.0 +/- 5.5 years for NVE versus 5.1 +/- 4.6 years for PVE, p = 0.191), and total follow up was 1,707.85 patient-years. Actuarial survival at 1, 5, 10 and 15 years was respectively 91, 82, 67.5 and 48.8% in NVE, and 79.7, 64.2, 33.5 and 33.5% in PVE (p = 0.0016). A significantly lower survival in PVE versus NVE was found for the mitral site subgroup (p = 0.018), but not for the aortic site (p = 0.14). Actuarial freedom from reoperation for recurrent endocarditis at 1, 5, 10 and 15 years was 97.5, 91.4, 80.5 and 49.4% in NVE versus 90.8, 84.9, 59.4 and 43.9% in PVE (p = 0.015). CONCLUSION: PVE patients were older, presented with more compromised clinical conditions, and had worse early and long-term outcomes than NVE patients. PVE had a higher incidence of recurrence and worse prognosis, especially if the mitral valve was involved.     

Single-center experience of a quadripolar pacing lead for cardiac resynchronization therapy

AIM

Recent studies have shown that a quadripolar left ventricular (LV) lead can result in low rates of dislocation and phrenic nerve stimulation (PNS) acutely and on medium-term follow-up in cardiac resynchronization therapy (CRT). We evaluated the outcomes of CRT patients in whom a quadripolar LV lead was implanted in our institution.

Methods

We studied 45 consecutive heart failure patients (75 % men; age, 70.3?±?9.0 years) following successful implantation of a quadripolar LV lead. Demographic and clinical data were collected preoperatively, and patients were followed up for 18.9 months.

Results

The implantation success rate was 100 %. Mean overall duration was 100.1?±?34.6 min, and X-ray exposure time was 13.20?±?13.5 min. The most distal effective pacing site was used as the final pacing configuration in all patients. Acute dislodgment requiring reoperation occurred before discharge in three cases (6.6 %). Six patients (13 %) suffered PNS during follow-up; we solved this problem by changing the stimulation vector. Three months after implantation, a mean of six out of ten effective sites (threshold <2.5 V at 1.5 ms, no PNS) per patient was recorded.

Conclusions

Over the relatively long term, the quadripolar LV lead was associated with excellent pacing thresholds and low rates of dislocation and PNS.     

Added predictive value of high uric acid for cardiovascular events in the Ambulatory Blood Pressure International Study

The prognostic value of uric acid (UA) for cardiovascular events (CVE) is still debated. Our purpose was to investigate the association between UA and CVE in 5243 participants of the ABP‐International study with the main aim of identifying optimal sex‐specific cut‐points. In multivariable Cox analyses, the relationship between CVE and UA as a continuous variable was modeled by including both linear and nonlinear terms. Survival models were also estimated with UA as a categorical variable. Optimal UA cut‐points were determined using an outcome‐oriented approach. During a median follow‐up of 5.9 years, there were 423 CVE (93 fatal). In age‐ and sex‐adjusted Cox models, UA as a continuous variable was a significant predictor of CVE in all individuals and in men and women considered separately. The relationship between UA and CVE was linear (P‐value for nonlinearity 0.54 and 0.80 for men and women, respectively). For each 1 mg/dL increase in UA, the relative hazard increase was 16% in men and 19% in women. In fully adjusted models, UA remained a significant predictor of CVE in the whole study cohort. The optimal cut‐point best separating patients at low and high risk of CVE was 6.3 mg/dL for men and 4.4 mg/dL for women. Subjects with high UA had a 38% greater risk of CVE. In a sex‐specific analysis, the association remained significant only in men (hazard ratio, 1.47; P < 0.01). In conclusion, high UA is an independent predictor for subsequent CVE and significantly improves risk discrimination and reclassification over the baseline multivariable model.     

Effect of oral contraceptives on endothelial function in the peripheral microcirculation of healthy women

OBJECTIVES: We assessed whether third-generation oral contraceptive (OC) treatment (30 microg ethinylestradiol + 75 microg gestodene daily) could affect the endothelial function of healthy women. METHODS: In 20 young healthy women (HW) and 10 hypercholesterolemic women (CW) we assessed forearm blood flow (strain-gauge plethysmography) changes induced by the intrabrachial infusion of acetylcholine (ACH) (0.15-15 microg/100 ml forearm tissue/min) and sodium nitroprusside (SNP) (1-4 microg/100 ml forearm tissue/min). ACH was repeated during the nitric oxide synthase inhibitor intra-arterial NG-monomethyl-L-arginine (L-NMMA) (100 microg/100 ml forearm tissue/min) or the antioxidant vitamin C (8 mg/100 ml forearm tissue/min). HW repeated the protocol after 6-month OC (n = 10) or placebo (n = 10) treatment. RESULTS: In HW the maximal vasodilation to ACH, similar between placebo and OC subgroups, was significantly reduced in CW (P < 0.01). Vasodilation to ACH was blunted (P < 0.01) by L-NMMA and unaffected by vitamin C, in both OC and placebo groups. In CW the vasodilation to ACH, not modified by L-NMMA, was improved by vitamin C (P < 0.01). OC treatment raised (P < 0.01) plasma total and low-density lipoprotein cholesterol, and values were similar to those shown by CW. Both OC and placebo intake did not change the response to ACH and the modulation induced by L-NMMA or vitamin C. Vasodilation to SNP was similar in all groups. CONCLUSIONS: In HW 6-month treatment with third-generation OC, although associated with an abnormal lipid profile, does not adversely affect endothelium-dependent vasodilation. This neutral effect could be the balance between a deleterious effect of hypercholesterolemia and a protective effect of OC on endothelial function.     

Long-term effects of losartan and enalapril, alone or with a diuretic, on ambulatory blood pressure and cardiac performance in hypertension: a case-control study

BACKGROUND: The long-term effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on ambulatory blood pressure and cardiac performance have never been examined comparatively. OBJECTIVE: We compared losartan and enalapril in their long-term effects on office and ambulatory blood pressure, cardiac structure and function, and routine biochemical tests. DESIGN: In the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study, 22 hypertensive subjects were studied with ambulatory blood pressure monitoring and echocardiography before and after an average of 3.3 years of treatment with losartan 50mg daily. These subjects were matched in a 1:3 ratio with a group of 66 subjects treated with enalapril 20mg daily. Case-control sampling was based on age (+/-5years), sex, pre-treatment office blood pressure (+/-5mmHg) and ambulatory blood pressure (+/-5mmHg), and duration of treatment (+/-6months). An additional group of subjects who interrupted their treatment with enalapril (n=18) or losartan (n =2) because of unwanted effects before execution of the follow-up study was not included in the analysis. RESULTS: Hydrochlorothiazide was added during follow-up in order to optimize blood pressure control (office blood pressure <140mmHg systolic and 90mmHg diastolic) in 10 subjects (45%) in the losartan group and 34 subjects (52%) in the enalapril group. Office and ambulatory blood pressures were lowered to a similar extent by losartan and enalapril. Left ventricular mass decreased from 98 to 87g/m(2) with losartan (P <0.01) and from 98 to 89 g/m(2) with enalapril (P <0.01). The change in left ventricular mass over time was more closely associated with the change in ambulatory blood pressure than with office blood pressure in both groups. Left ventricular internal diameter did not change with either drug. The endocardial shortening fraction, mid-wall shortening fraction and Doppler indexes of active diastolic relaxation did not change with either drug. None of the biochemical parameters showed a significant change. Serum uric acid showed a slight and non-significant reduction only in the losartan group. CONCLUSION: In this case-control study in uncomplicated subjects with essential hypertension, losartan and enalapril, alone or combined with a diuretic, effectively and equally lowered office and ambulatory blood pressure and induced a significant reduction in left ventricular mass during long-term treatment. Left ventricular systolic and diastolic function remained unchanged with either regimen.     

Trends in hypertension management in Type I diabetes across Europe, 1989/1990 - 1997/1999

Aims/hypothesis Our aim was to examine the change in the management of hypertension in patients with Type I (insulin-dependent) diabetes mellitus in Europe, between 1989–1990 and 1997–1999.Methods Seven-year changes in hypertension treatment and control (defined as blood pressure <130/85 mmHg) were examined in a large sample of Type I diabetic patients recruited from 26 centres involved in the EURODIAB Prospective Complications Study. Hypertension was defined as a systolic and/or diastolic blood pressure greater than 140 and/or 90 mmHg respectively, and/or use of blood pressure lowering drugs.Results Of 1866 Type I diabetic patients, 412 had hypertension at baseline and 631 at follow-up. A greater proportion of hypertensive patients were treated at follow-up (69% vs 40%, p<0.0001), which persisted after adjustment for age or centre. Of those who were treated, a modest increase in the proportion of those controlled for hypertension was found (41% vs 32%, p=0.048), which disappeared after adjustment for age. Among hypertensive patients with albuminuria, the proportions treated also increased, from 35% to 76% (p<0.0001) in microalbuminuric and 64% to 95% (p<0.0001) in macroalbuminuric patients. Control of hypertension in albuminuric patients did not change significantly and was below 50%. The use of more than one anti-hypertensive drug increased over a 7-year period, from 19% to 33% (p<0.0001), and a marked increase was shown in the proportion of those taking an ACE inhibitor (from 57% to 82%, p<0.0001).Conclusion/interpretation The management of hypertension in Type I diabetic patients across Europe has improved over a 7-year follow-up period. Optimal levels of blood pressure treatment and optimal levels of control have not yet been achieved.Abbreviations CCB Calcium channel blockerAn erratum to this article can be found at     

Hepatic clearance ofd-sorbitol

The hepatic clearance ofd-sorbitol, a natural polyol which is metabolized by the liver, was studied in normal and cirrhotic subjects after bolus intravenous injection (2 g) and during constant infusion (54 mg/min) with the aim of providing a noninvasive and simple measure of functional liver plasma flow. The high hepatic extraction ofd-sorbitol and the dose-independence of its clearance pointed to a flow-dependent clearance regimen. The renal excretion was taken into account when computing the hepatic clearance. Day-today reproducibility of the test was good. No significant difference was found when the hepatic clearance was measured by bolus injection or constant infusion methods. As measured by the bolus injection method, the mean (±sd) hepatic clearance in the normal subjects (911±137 ml/min) was significantly greater (P<0.001) than that of the cirrhotics (456±181 ml/min).This study was partially supported by grants from Consiglio Nazionale Ricerche (84.01760.04) and Ministero Pubblica Istruzione (2.12.2).     

Short-term effects of transjugular intrahepatic portosystemic shunt (TIPS) on functional liver plasma flow in patients with advanced cirrhosis

ABSTRACT— Aims/Background: TIPS, an effective procedure applied for the treatment of complications of portal hypertension, is potentially followed by worsening of the hyperdynamic circulation of cirrhosis and the impairment of liver function. The aim of the present study was to evaluate short-term changes of functional liver plasma flow after application of TIPS, using the hepatic (extrarenal) clearance of D-sorbitol (S-HCl). Methods: Twenty-five cirrhotic patients submitted to TIPS for prevention of variceal rebleeding entered the study. At steady-state, during constant infusion of a solution of D-sorbitol (25 mg/min), appropriate blood and urine samples were collected in order to calculate S-HCl before and 120 min after TIPS opening. In addition, the hepatic extraction ratio of D-sorbitol was directly measured at the level of the right (E_r), where TIPS was applied, and of the left (E_l) hepatic veins; meanwhile the portocaval gradient (PCG) was registered, before and after stent dilation. A comparison of values obtained before and after TIPS application was performed by Student's t-test for paired data. Results: After application of TIPS, a substantial reduction was observed in PCG (12.1 ± 4.2 vs 24.8 ± 4.3 mmHg; p<0.001) and E_r values (20.6 ± 14.8 vs 57.5 ± 22.3%; p<0.001) but not E_l values (47.4 ± 22.0 vs 53.4 ± 21.4%; p=0.178). S-HCl measured 120 min after TIPS opening was not statistically different from pre-TIPS values (389.2 ± 212.1 vs 394.6 ± 152.7 ml/min; p=0.892), although S-HCl variations in Child-Pugh class B patients were positively correlated with portal pressure variations (r=0.63, p=0.016). Conclusion: Our results demonstrate that in patients with advanced cirrhosis, TIPS procedure, while effective in reducing portal hypertension, does not lead to alterations in the functional liver plasma flow within the first 2 h.