Jaffe, Allan S.

Abstract Background: We investigated whether higher concentrations of N-terminal pro–B-type natriuretic peptide (NT-proBNP) predicts cardiovascular adverse events (CV-AEs) in patients with osteoarthritis treated with antiinflammatory drugs. Methods: NT-proBNP was measured in baseline samples from 433 patients enrolled in a prospective randomized study designed to test the therapeutic effect of a novel metalloproteinase inhibitor. We monitored CV-AEs and retrospectively investigated their relationship to the concomitant use of selective cyclooxygenase-2 inhibitors (coxibs), traditional nonsteroidal antiinflammatory drugs (tNSAIDs), and glucocorticoids. CV-AEs included myocardial infarction, stroke, new or worsening of preexisting arterial hypertension, congestive heart failure, and several less severe CV-AEs. Results: We observed 82 mild to serious CV-AEs during an observational period of 200 days. The risk of such events was 1.95-fold higher in patients who were taking tNSAIDs, glucocorticoids, or coxibs (i.e., any inhibitor) and who had NT-proBNP concentrations ≥100 ng/L than in patients taking any inhibitor who had NT-proBNP values <100 ng/L (P < 0.05). Patients taking coxibs (alone or in addition to tNSAIDs or glucocorticoids) with baseline NT-proBNP values ≥100 ng/L had a 7.41-fold higher risk for CV-AEs than those with baseline values <100 ng/L (P < 0.01). Patients who were taking 2 or more antiinflammatory drugs and had NT-proBNP values ≥100 ng/L had a 3.74-fold higher risk for CV-AEs than those with NT-proBNP values <100 ng/L (P < 0.05). An NT-proBNP value <100 ng/L was associated with negative predictive values of >85% across all treatment groups. Conclusions: NT-proBNP may be a useful marker for anticipating cardiovascular risk associated with the use of antiinflammatory drugs for osteoarthritis.

Abstract Background: We evaluated the sensitivity, precision, and concordance of 4 assays designed to detect aspirin responsiveness or resistance. Methods: Twenty-nine healthy laboratory volunteers took 80 mg aspirin for 7 days, and a subset of volunteers took 325 mg aspirin for an additional 7 days. We measured platelet function by light transmission aggregometry with arachidonic acid, PFA-100, and VerifyNow. PFA-100 and VerifyNow assays were performed in duplicate to assess method imprecision. Some volunteers had samples taken within 2–4 h of the final dose of aspirin and again within 20–24 h of the final dose. We measured urinary 11-dehydro-thromboxane B2 at baseline and after 80 or 325 mg aspirin. Results: No volunteers were nonresponsive to aspirin therapy as measured by the PFA-100. One of 29 participants demonstrated lack of response to aspirin as measured by VerifyNow and urinary 11-dehydro-thromboxane B2; 2 of 29 demonstrated lack of response as measured by light transmission aggregometry. Imprecision was <10% for the PFA-100 and VerifyNow. Concordance was high (>90%) between all assays. Neither aspirin dose (80 vs 325 mg) nor timing between final dose of aspirin and blood draw (2–4 vs 20–24 h) affected any of the assays. Conclusions: Light transmission aggregometry, PFA-100, VerifyNow, and urinary 11-dehydro-thromboxane B2 are all sensitive to the effects of aspirin in healthy individuals. Variables such as aspirin dose, timing between final dose of aspirin and blood collection, and imprecision do not affect the ability of the assays to detect aspirin effect on platelet function.

Abstract Background: Guidelines for treatment of acute coronary syndrome (ACS) recommend observing a rise or fall in cardiac troponin (cTn) concentrations for assessing acute injury. It is unknown whether a rising pattern presages a more adverse long-term prognosis than elevations that do not change. The present study assessed whether a rising pattern of cardiac biomarkers was more prognostic than simple elevations. Methods: We measured N-terminal pro-brain natriuretic peptide (NT-proBNP) (Roche), cTnT (Roche) and cTnI (Beckman Coulter) in 212 ACS patients. These biomarkers were measured in coincident EDTA and heparin plasma samples available from at least 2 different time points, an early first specimen obtained a median of 2 hours after onset of symptoms, interquartile range (IQR) 2–4 hours, and a later second specimen obtained at 9 hours, IQR 9–9 hours. The cTn concentration in the second specimen was used to classify myocardial necrosis (cTnI >0.04 ug/L; cTnT >0.01 ug/L). Outcomes [death, myocardial infarction (MI), heart failure (HF)] were obtained >8 years after the initial presentation. For patients with myocardial necrosis and a cTn concentration ratio (second/first measured concentrations) ≥1.00, the concentration ratios and the absolute concentrations in the second specimen were used to assess prognosis after 4 years. Results: In myocardial necrosis, the relative change (cTn2/cTn1) was greater for cTnI than for cTnT (P <0.01), whereas the relative change in NT-proBNP was the same regardless of which troponin was used to classify necrosis (P = 0.71). The concentration ratio for cTnI, cTnT, and NT-proBNP was not useful for risk stratification (i.e., death/MI/HF; P ≥0.15). Conclusions: A rise in cardiac troponin or NT-proBNP concentration in ACS patients presenting early after onset of pain is not helpful for long-term prognosis.

Purpose To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial. Patients and Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months. Results Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%. Conclusion The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.