Faculty Bibliography

Background: Prasugrel is effective at decreasing cardiovascular events compared to clopidogrel, but increases the risk of bleeding. In 2010, the FDA issued a black box warning to consider genetic testing in clopidogrel users. Our aims were to evaluate (1) the balance of potential benefits and harms and (2) the cost-effectiveness that would result from adopting a genotype-guided strategy of dual anti-platelet therapy following PCI for ACS vs. no testing strategies of prasugrel plus aspirin (prasugrel) or clopidogrel plus aspirin (clopidogrel). Methods: A Markov state transition model was used to conduct a decision analysis and compare strategies. Probabilities of adverse outcomes were derived from TRITON-TIMI 38 trial. Event rates on clopidogrel for carriers of CYP2C19*2 vs. wild-type were derived from the TRITON genetic substudy and a recent meta-analysis. Costs are expressed in January 2011 US dollars and estimated based on Medicare reimbursements for diagnosis-related group codes. Medication costs were used from the net wholesale price for prasugrel ($5.45/d) and a generic estimate for clopidogrel ($1/d). Results: In base case analyses, the genetic testing guided strategy yielded more benefits than harms, and was less costly compared to both 'no testing' strategies. Over 15 months, total costs were $83.8 ($1200.9 at 10 yrs) lower with a gain of 0.0007 QALY (0.0216 QALY at 10 yrs) in the genotype-guided strategy compared to prasugrel. Compared to clopidogrel, it was $0.38 ($2168.8 at 10 yrs) lower with a gain of 0.0036 QALY (0.112 QALY at 10 yrs). The strongest predictor of the preferred strategy was the relative risk (RR) of a thrombotic event occurring in CYP2C19*2 carriers versus wild-type. Below a RR of 1.5, a genotype-guided strategy is no longer more effective (but is less expensive) when compared to prasugrel. Compared to clopidogrel, below a RR of 1.3 a genotype-guided strategy is no longer cost effective (>$100,000/QALY). Clopidogrel costs ($1-$4/d) did not alter our results. Conclusions: Among ACS patients undergoing PCI, a genotype-guided strategy is economically favorable in determining which anti-platelet regimen is used, assuming that the risk of thrombotic events in CYP2C19*2 carriers is approximately 30-50% higher than wild type patients

BACKGROUND: Whether myocardial perfusion grade (MPG) following late recanalization of infarct-related arteries (IRAs) predicts left ventricular (LV) function recovery beyond the acute phase of myocardial infarction (MI) is unknown. METHODS AND RESULTS: The Total Occlusion Study of Canada-2 enrolled stable patients with a persistently occluded IRA beyond 24 hours and up to 28 days post-MI. We studied the relationship between the initial MPG and changes in LV function and volume as well as the change in MPG from immediate post-percutaneous coronary intervention (PCI) to 1 year in 139 PCI patients with thrombolysis in myocardial infarction grade 3 epicardial flow post-PCI and with paired values grouped into impaired or good MPG groups (MPG 0/1 or MPG 2/3). MPG 0/1 patients were more likely to have received thrombolytic therapy and to have a left anterior descending IRA. They had lower blood pressure and LV ejection fraction (LVEF) and a higher heart rate and systolic sphericity index at baseline. Changes in the MPG 0/1 and MPG 2/3 groups from baseline to 1 year were LVEF, 3.3+/-9.0% and 4.8+/-8.9% (P=0.42); LV end-systolic volume index (LVESVI), -1.1+/-9.2 and -4.7+/-12.3 mL/m(2) (P=0.25); LV end-diastolic volume index (LVEDVI), 0.08+/-19.1 and -2.4+/-22.2 mL/m(2) (P=0.67); and SDs/chord for infarct zone wall motion index (WMI), 0.38+/-0.70 and 0.84+/-1.11 (P=0.01). By covariate-adjusted analysis, post-PCI MPG 0/1 predicted lower WMI (P<0.001), lower LVEF (P<0.001), and higher LVESVI (P<0.01) but not LVEDVI at 1 year. Of the MPG 0/1 patients, 60% were MPG 2 or 3 at 1 year. CONCLUSIONS: Preserved MPG is present in a high proportion of patients following late PCI of occluded IRAs post-MI. Poor MPG post-PCI frequently improves MPG over 1 year. MPG graded after IRA recanalization undertaken days to weeks post MI is associated with LV recovery, indicating that MPG determined in the subacute post-MI period remains a marker of viability. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00025766

BACKGROUND: The role of hormone replacement therapy (HRT) in the prevention of cardiovascular disease has been controversial. In large observational studies, HRT appears to lower cardiovascular disease risk. However, prospective randomized trials do not substantiate this. METHODS: We sought to characterize the use of HRT in women presenting with acute myocardial infarction and to investigate an association between HRT and inhospital or 30-day outcomes among women enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries III (GUSTO-III) trial. Of the 15,059 patients in GUSTO-III, 4124 were women. Menopausal status, HRT use, and clinical outcomes data were prospectively collected. RESULTS: Postmenopausal women taking HRT were significantly younger than those not taking HRT, and US women were more likely to be prescribed HRT than non-US women. While unadjusted 30-day mortality was substantially lower in HRT patients (6.1% vs 12.7%, P < .001), HRT use was not independently predictive of mortality after correcting for baseline differences (chi(2) = 0.15, P = .70). CONCLUSION: Hormone replacement therapy appears to have no early mortality benefit in women sustaining acute myocardial infarction. These findings further challenge the role of HRT in cardiovascular medicine

BACKGROUND: Early revascularization (ERV) is beneficial in the management of cardiogenic shock (CS) complicating myocardial infarction. The severity of CS varies widely, and identification of independent risk factors for outcome is needed. The effect of ERV on mortality in different risk strata is also unknown. We created a severity scoring system for CS and used it to examine the potential benefit of ERV in different risk strata using data from the SHOCK Trial and Registry. METHODS: Data from 1,217 patients (294 from the randomized trial and 923 from the registry) with CS due to pump failure were included in a Stage 1 severity scoring system using clinical variables. A Stage 2 scoring system was developed using data from 872 patients who had invasive hemodynamic measurements. The outcome was in-hospital mortality at 30 days. RESULTS: In-hospital mortality at 30 days was 57%. Multivariable modeling identified 8 risk factors (Stage 1): age, shock on admission, clinical evidence of end-organ hypoperfusion, anoxic brain damage, systolic blood pressure, prior coronary artery bypass grafting, noninferior myocardial infarction, and creatinine > or = 1.9 mg/dL (c-statistic = 0.74). Mortality ranged from 22% to 88% by score category. The ERV benefit was greatest in moderate- to high-risk patients (P = .02). The Stage 2 model based on patients with pulmonary artery catheterization included age, end-organ hypoperfusion, anoxic brain damage, stroke work, and left ventricular ejection fraction <28% (c-statistic = 0.76). In this cohort, the effect of ERV did not vary by risk stratum. CONCLUSIONS: Simple clinical predictors provide good discrimination of mortality risk in CS complicating myocardial infarction. Early revascularization is associated with improved survival across a broad range of risk strata

BACKGROUND: A substantial minority of patients with acute coronary syndromes (ACS) do not have a diameter stenosis of any major epicardial coronary artery on angiography ('no obstruction at angiography') of >/= 50%. We examined the frequency of this finding and its relationship to race and sex. HYPOTHESIS: Among patients with myocardial infarction, younger age, female sex and non-white race are associated with the absence of obstructive coronary artery disease at angiography. METHODS: We reviewed the results of all angiograms performed from May 19, 2006 to September 29, 2006 at 1 private (n = 793) and 1 public (n = 578) urban academic medical center. Charts were reviewed for indication and results of angiography, and for demographics. RESULTS: The cohort included 518 patients with ACS. There was no obstruction at angiography in 106 patients (21%), including 48 (18%) of 258 patients with myocardial infarction. Women were more likely to have no obstruction at angiography than men, both in the overall cohort (55/170 women [32%] vs 51/348 men [15%], P < 0.001) and in the subset with MI (29/90 women [32%] vs 19/168 men [11%], P < 0.001). Black patients were more likely to have no obstruction at angiography relative to any other subgroup (24/66 [36%] vs 41/229 [18%] Whites, 31/150 [21%] Hispanics, and 5/58 [9%] Asians, P = 0.001). Among women, Black patients more frequently had no obstruction at angiography compared with other ethnic groups (16/27 [59%] vs 17/59 [29%] Whites, 17/60 [28%] Hispanics, and 3/19 [6%] Asians, P = 0.001). CONCLUSIONS: A high proportion of a multiethnic sample of patients with ACS were found to have no stenosis >/= 50% in diameter at coronary angiography. This was particularly common among women and Black patients.

BACKGROUND: Collateral flow to the infarct artery territory after acute myocardial infarction may be associated with improved clinical outcomes and may also impact the benefit of subsequent recanalization of an occluded infarct-related artery. METHODS AND RESULTS: To understand the association between baseline collateral flow to the infarct territory on clinical outcomes and its interaction with percutaneous coronary intervention of an occluded infarct artery, long-term outcomes in 2173 patients with total occlusion of the infarct artery 3 to 28 days after myocardial infarction from the randomized Occluded Artery Trial were analyzed according to angiographic collaterals documented at study entry. There were important differences in baseline clinical and angiographic characteristics as a function of collateral grade, with generally lower-risk characteristics associated with higher collateral grade. Higher collateral grade was associated with lower rates of death (P=0.009), class III and IV heart failure (P<0.0001) or either (P=0.0002) but had no association with the risk of reinfarction. However, by multivariate analysis, collateral flow was neither an independent predictor of death nor of the primary end point of the trial (composite of death, reinfarction, or class IV heart failure). There was no interaction between angiographic collateral grade and the results of randomized treatment assignment (percutaneous coronary intervention or medical therapy alone) on clinical outcomes. CONCLUSIONS: In recent myocardial infarction, angiographic collaterals to the occluded infarct artery are correlates but not independent predictors of major clinical outcomes. Late recanalization of the infarct artery in addition to medical therapy shows no benefit compared with medical therapy alone, regardless of the presence or absence of collaterals. Therefore, revascularization decisions in patients with recent myocardial infarction should not be based on the presence or grade of angiographic collaterals. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004562

BACKGROUND: The pathobiological basis of ischemic heart disease and thus the manifestations and response to therapy can differ between women and men. In prior studies, sex-based treatment differences have been observed with the antiischemic ranolazine, with a possibly diminished effect in women. METHODS AND RESULTS: We conducted a prospectively planned analysis of the clinical, biomarker, angiographic, and continuous ECG features and 1-year outcomes of women with unstable ischemic heart disease randomized to ranolazine or placebo in Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36). Compared with men (n=4269), women (n=2291) were older with more risk factors (P<0.001). On presentation, women were less likely than men to have significant epicardial coronary artery disease (no stenosis >or=50% on angiography, 19.4% versus 8.6%; P<0.001) or elevated troponin (57.1% versus 68.9%; P<0.001). Yet, women were more likely to have an elevated B-type natriuretic peptide (47.0% versus 40.2%; P<0.001), worse median angina frequency scores (80 versus 100; P<0.001), and an ischemic episode on continuous ECG administered during the first 7 days (22.5% versus 19.3%; P=0.0025). Women and men were at similar adjusted risk for the primary end point of cardiovascular death, myocardial infarction, or recurrent ischemia (adjusted hazard ratio, 1.11; 95% confidence interval, 0.96 to 1.29; P=0.15). Ranolazine was associated with a significant reduction in recurrent ischemia in women (13.0% versus 18.2%; hazard ratio, 0.71; 95% confidence interval, 0.57 to 0.88; P=0.002). CONCLUSIONS: Women with a clinical syndrome consistent with unstable ischemic heart disease, despite having less obstructive coronary artery disease, were more likely than men to report anginal episodes and had more recorded ischemic periods on continuous ECG. In this setting, ranolazine may be a particularly useful antiischemic agent in women. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00099788