Giovanni Parrinello

Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure

Background— Circulating cardiac troponin T, a marker of cardiomyocyte injury, predicts adverse outcome in patients with heart failure (HF) but is detectable in only a small fraction of those with chronic stable HF. We assessed the prognostic value of circulating cardiac troponin T in patients with stable chronic HF with a traditional (cTnT) and a new precommercial highly sensitive assay (hsTnT). Methods and Results— Plasma troponin T was measured in 4053 patients with chronic HF enrolled in the Valsartan Heart Failure Trial (Val-HeFT). Troponin T was detectable in 10.4% of the population with the cTnT assay (detection limit ≤0.01 ng/mL) compared with 92.0% with the new hsTnT assay (≤0.001 ng/mL). Patients with cTnT elevation or with hsTnT above the median (0.012 ng/mL) had more severe HF and worse outcome. In Cox proportional hazards models adjusting for clinical risk factors, cTnT was associated with death (780 events; hazard ratio=2.08; 95% confidence interval, 1.72 to 2.52; P<0.0001) and first hospitalization for HF (655 events; hazard ratio=1.55; 95% confidence interval, 1.25 to 1.93; P<0.0001). HsTnT was associated with the risk of death in unadjusted analysis for deciles of concentrations and in multivariable models (hazard ratio=1.05; 95% confidence interval, 1.04 to 1.07 for increments of 0.01 ng/mL; P<0.0001). Addition of hsTnT to well-calibrated models adjusted for clinical risk factors, with or without brain natriuretic peptide, significantly improved prognostic discrimination (C-index, P<0.0001 for both outcomes). Conclusions— In this large population of patients with HF, detectable cTnT predicts adverse outcomes in chronic HF. By the highly sensitive assay, troponin T retains a prognostic value at previously undetectable concentrations.

Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting A Randomized Multicenter Trial

Background— The optimal duration of dual-antiplatelet therapy and the risk-benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined. We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration–approved drug-eluting or bare-metal stents. Methods and Results— We randomly assigned 2013 patients to receive bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation. At 30 days, patients in each stent group were randomly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin. The primary end point was a composite of death of any cause, myocardial infarction, or cerebrovascular accident. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74–1.29; P=0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. Conclusions— A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause, myocardial infarction, or cerebrovascular accident. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00611286.

Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome.

OBJECTIVES This study sought to investigate the evolving pattern over time of on-clopidogrel platelet reactivity (PR) and its relationship with genotype and clinical outcomes after percutaneous coronary intervention. BACKGROUND Whether on-clopidogrel PR and role of genotype differ over time is unknown. METHODS On-clopidogrel PR before percutaneous coronary intervention, and 1 and 6 months thereafter via VerifyNow P2Y12 (Accumetrics Inc., San Diego, California), CYP2C19*2, *17, CYP3A5*3, and ABCB1 polymorphisms were evaluated in 300 patients. Death, stroke, myocardial infarction, and bleedings were assessed up to 1 year. RESULTS On-clopidogrel PR varied significantly over time, being higher at baseline than at 1 and 6 months after. From baseline to 1 month, 83 of 300 patients varied their response status. This was mainly due to baseline poor responders becoming full responders (75 of 83). Genotype justifies roughly 18% of this trend. CYP2C19*2 and *17 influence on PR was consistent over time, whereas that of ABCB1 appeared of greater impact at baseline. On-clopidogrel PR at 1 month independently best predicts ischemic and bleeding events. We found a therapeutic window (86 to 238 P2Y₁₂ reactivity units) with a lower incidence of both ischemic and bleeding complications. A risk score was created by combining genotype (ABCB1 and CYP2C19*2), baseline PR, and creatinine clearance to predict 1-month poor responsiveness and 1-year poor prognosis. CONCLUSIONS In patients at steady state for clopidogrel undergoing percutaneous coronary intervention, PR decreases from baseline to 1 month. Genotype influences ≈18% of this trend. On-clopidogrel PR at 1 month is the strongest predictor of adverse outcomes, and this can be predicted by combining genotype to baseline phenotype and clinical variables.

Worsening renal function in patients hospitalised for acute heart failure: Clinical implications and prognostic significance

Renal function is a powerful prognostic variable in patients with heart failure (HF). Hospitalisations for acute HF (AHF) may be associated with further worsening of renal function (WRF).

Comparison of Angioplasty With Infusion of Tirofiban or Abciximab and With Implantation of Sirolimus-Eluting or Uncoated Stents for Acute Myocardial Infarction: The MULTISTRATEGY Randomized Trial

CONTEXT Abciximab infusion and uncoated-stent implantation is a complementary treatment strategy to reduce major adverse cardiac events in patients undergoing angioplasty for ST-segment elevation myocardial infarction (STEMI). It is uncertain whether there may be similar benefits in replacing abciximab with high-dose bolus tirofiban. Similarly, the use of drug-eluting stents in this patient population is currently discouraged because of conflicting results on efficacy reported in randomized trials and safety concerns reported by registries. OBJECTIVE To evaluate the effect of high-dose bolus tirofiban and of sirolimus-eluting stents as compared with abciximab infusion and uncoated-stent implantation in patients with STEMI undergoing percutaneous coronary intervention. DESIGN, SETTING, AND PATIENTS An open-label, 2 x 2 factorial trial of 745 patients presenting with STEMI or new left bundle-branch block at 16 referral centers in Italy, Spain, and Argentina between October 2004 and April 2007. INTERVENTIONS High-dose bolus tirofiban vs abciximab infusion and sirolimus-eluting stent vs uncoated stent implantation. MAIN OUTCOME MEASURES For drug comparison, at least 50% ST-segment elevation resolution at 90 minutes postintervention with a prespecified noninferiority margin of 9% difference (relative risk, 0.89); for stent comparison, the rate of major adverse cardiac events, defined as the composite of death from any cause, reinfarction, and clinically driven target-vessel revascularization within 8 months. RESULTS ST-segment resolution occurred in 302 of 361 patients (83.6%) who had received abciximab infusion and 308 of 361 (85.3%) who had received tirofiban infusion (relative risk, 1.020; 97.5% confidence interval, 0.958-1.086; P < .001 for noninferiority). Ischemic and hemorrhagic outcomes were similar in the tirofiban and abciximab groups. At 8 months, major adverse cardiac events occurred in 54 patients (14.5%) with uncoated stents and 29 (7.8%) with sirolimus stents (P = .004), predominantly reflecting a reduction of revascularization rates (10.2% vs 3.2%). The incidence of stent thrombosis was similar in the 2 stent groups. CONCLUSIONS In patients with STEMI undergoing percutaneous coronary intervention, compared with abciximab, tirofiban therapy was associated with noninferior resolution of ST-segment elevation at 90 minutes following coronary intervention, whereas sirolimus-eluting stent implantation was associated with a significantly lower risk of major adverse cardiac events than uncoated stents within 8 months after intervention. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00229515.

Intensifying Platelet Inhibition With Tirofiban in Poor Responders to Aspirin, Clopidogrel, or Both Agents Undergoing Elective Coronary Intervention Results From the Double-Blind, Prospective, Randomized Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel Study

Background— Inhibition of platelet aggregation after aspirin or clopidogrel intake varies greatly among patients, and previous studies have suggested that poor response to oral antiplatelet agents may increase the risk of thrombotic events, especially after coronary angioplasty. Whether this reflects suboptimal platelet inhibition per se, which might benefit from more potent antiplatelet agents such as tirofiban, is unknown. Methods and Results— We screened 1277 patients to enroll 93 aspirin, 147 clopidogrel, and 23 dual poor responders, based on a point-of-care assay, who underwent elective coronary angioplasty at 10 European sites for stable or low-risk unstable coronary artery disease. Patients were randomly assigned in a double-blind manner to receive either tirofiban (n=132) or placebo (n=131) on top of standard aspirin and clopidogrel therapy. The primary end point, consisting of troponin I/T elevation at least 3 times the upper limit of normal, was attained in 20.4% (n=27) in the tirofiban group compared with 35.1% (n=46) in the placebo group (relative risk, 0.58; 95% confidence interval, 0.39 to 0.88; P=0.009). The rate of major adverse cardiovascular events within 30 days in the tirofiban group also was reduced (3.8% versus 10.7%; P=0.031). The overall incidence of bleeding was low, likely explained by a substantial use of the transradial approach, and did not differ between the 2 groups. Conclusions— In low-risk patients according to clinical presentation who had poor responsiveness to standard oral platelet inhibitors via a point-of-care assay, intensified platelet inhibition with tirofiban lowers the incidence of myocardial infarction after elective coronary intervention.

Serum From Patients With Severe Heart Failure Downregulates eNOS and Is Proapoptotic Role of Tumor Necrosis Factor-α

BACKGROUND Cytokine activation and endothelial dysfunction are typical phenomena of congestive heart failure (CHF). We tested the hypothesis that incubating human umbilical vein endothelial cells with serum from patients with CHF will downregulate endothelial constitutive nitric oxide synthase (eNOS) and induce apoptosis. METHODS AND RESULTS We studied 21 patients with severe CHF. Levels of tumor necrosis factor-alpha (TNF-alpha) and several neuroendocrine parameters were assessed. eNOS was measured by Western Blot analysis and apoptosis by optical microscopy and flow cytometry. We observed (1) eNOS downregulation (difference versus healthy subjects at 24 hours [P<0.05] and 48 hours [P<0.001]), (2) nuclear morphological changes typical of apoptosis; and (3) a high apoptotic rate with propidium iodide (increasing from 2.1+/-0.4% to 11.3+/-1.2% at 48 hours; P<0.001 versus healthy subjects) and annexin V. An anti-human TNF-alpha antibody did not completely counteract these effects. A strong correlation existed between eNOS downregulation and apoptosis (r = -0.89; P<0.001). CONCLUSIONS Serum from patients with severe CHF downregulates eNOS expression and increases apoptosis. High levels of TNF-alpha likely play a role, but they cannot be the only factor responsible.

Tumor Necrosis Factor-α Receptor 1 Is a Major Predictor of Mortality and New-Onset Heart Failure in Patients With Acute Myocardial Infarction The Cytokine-Activation and Long-Term Prognosis in Myocardial Infarction (C-ALPHA) Study

Background—Tumor necrosis factor alpha-&agr; (TNF-&agr;) activation is an independent prognostic indicator of mortality in patients with heart failure (HF). Despite the recognition that several TNF family cytokines are elevated during myocardial infarction, their role in predicting subsequent prognosis in these setting remains poorly understood. Methods and Results—We performed a systematic evaluation of TNF-&agr; and its type 1 and 2 soluble receptors, together with interleukin (IL)-6, IL-1 receptor antagonist, and IL-10, in 184 patients (132 men; mean age, 64±12) consecutively admitted for myocardial infarction. We correlated their values to short- and long-term incidence of death and HF (primary outcome). In 10 patients, we also studied the presence of transcardiac gradients for TNF-&agr; and its soluble receptors. The control group comprised 45 healthy subjects who were sex and age matched (33 men; mean age, 65±6 years) to the patients. All tested cytokines were increased in patients, and no transcardiac or systemic AV difference was found. After a median follow-up of 406 days (range, 346 to 696 days), 24 patients died and 32 developed HF. Univariate analysis showed that all cytokines were related to outcome, whereas after adjustment for baseline and clinical characteristics, sTNFR-1 remained the only independent predictor of death and HF (hazard ratio, 2.9; 95% CI, 1.9 to 3.8, tertile 1 versus 3), together with left ventricular ejection fraction, Killip class, and creatine kinase-MB at peak. Conclusions—sTNFR-1 is a major short- and long-term predictor of mortality and HF in patients with acute myocardial infarction.

The role of plasma biomarkers in acute heart failure. Serial changes and independent prognostic value of NT‐proBNP and cardiac troponin‐T

Brain natriuretic peptide (BNP), NT‐proBNP and troponins are useful for the assessment of patients with heart failure. Few data exist about their serial changes and their prognostic value in patients with acute heart failure (AHF).

Postlaryngectomy pharyngocutaneous fistula: incidence, predisposing factors, and therapy.

Pharyngocutaneous fistula is the most common complication following total laryngectomy. The present study was designed to determine the incidence and predisposing factors and to describe the management of the complication.