Faculty Bibliography

OBJECTIVES: To evaluate the efficacy and safety of drug eluting stents (DES) when compared with bare metal stents (BMS) in patients with moderate to severe calcified coronary lesions. BACKGROUND: Calcified coronary lesions present unique technical challenges during percutaneous coronary intervention (PCI) and it is not known if DES are as safe and as effective in the presence of calcium, as randomized trials typically exclude this common patient subset. METHODS: We evaluated patients with PCI of a single calcified lesion enrolled across five recruitment waves in the National Heart, Lung, and Blood Institute Dynamic Registry between 1997 and 2006. Patients were divided into two groups based on the stent type- BMS and DES. The primary efficacy outcome was the need for repeat revascularization at 1 year and the primary safety outcome was a composite of death and myocardial infarction at 1 year. RESULTS: Among the 1,537 patients included in the analysis, 884 (57%) underwent PCI with BMS and 653 (43%) with DES. DES use was associated with a significant reduction in the risk of repeat revascularization (10.0% vs. 15.3%; P = 0.003) with no significant higher risk of primary safety outcome (9.3% vs. 10.5%; P = 0.45) when compared to the BMS group. In a propensity score adjusted analysis, DES use was associated with a significantly lower risk in repeat revascularization (HR = 0.57; 95% CI 0.40-0.82; P = 0.002) and no significant difference in the risk of death and myocardial infarction (HR = 0.78; 95% CI 0.53-1.15; P = 0.20) compared to BMS group. CONCLUSION: In this large multicenter registry of patients with a moderate to severe calcified coronary lesion, use of DES compared to BMS was associated with significant reduction in the risk of repeat revascularization without any increase in death and myocardial infarction

BACKGROUND: The risk of cancer from antihypertensive drugs has been much debated, with a recent analysis showing increased risk with angiotensin-receptor blockers (ARBs). We assessed the association between antihypertensive drugs and cancer risk in a comprehensive analysis of data from randomised clinical trials. METHODS: We undertook traditional direct comparison meta-analyses, multiple comparisons (network) meta-analyses, and trial sequential analyses. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from 1950, to August, 2010, for randomised clinical trials of antihypertensive therapy (ARBs, angiotensin-converting-enzyme inhibitors [ACEi], beta blockers, calcium-channel blockers [CCBs], or diuretics) with follow-up of at least 1 year. Our primary outcomes were cancer and cancer-related deaths. FINDINGS: We identified 70 randomised controlled trials (148 comparator groups) with 324 168 participants. In the network meta-analysis (fixed-effect model), we recorded no difference in the risk of cancer with ARBs (proportion with cancer 2.04%; odds ratio 1.01, 95% CI 0.93-1.09), ACEi (2.03%; 1.00, 0.92-1.09), beta blockers (1.97%; 0.97, 0.88-1.07), CCBs (2.11%; 1.05, 0.96-1.13), diuretics (2.02%; 1.00, 0.90-1.11), or other controls (1.95%, 0.97, 0.74-1.24) versus placebo (2.02%). There was an increased risk with the combination of ACEi plus ARBs (2.30%, 1.14, 1.02-1.28); however, this risk was not apparent in the random-effects model (odds ratio 1.15, 95% CI 0.92-1.38). No differences were detected in cancer-related mortality for ARBs (death rate 1.33%; odds ratio 1.00, 95% CI 0.87-1.15), ACEi (1.25%; 0.95, 0.81-1.10), beta blockers (1.23%; 0.93, 0.80-1.08), CCBs (1.27%; 0.96, 0.82-1.11), diuretics (1.30%; 0.98, 0.84-1.13), other controls (1.43%; 1.08, 0.78-1.46), and ACEi plus ARBs (1.45%; 1.10, 0.90-1.32). In direct comparison meta-analyses, similar results were recorded for all antihypertensive classes, except for an increased risk of cancer with ACEi and ARB combination (OR 1.14, 95% CI 1.04-1.24; p=0.004) and with CCBs (1.06, 1.01-1.12; p=0.02). However, we noted no significant differences in cancer-related mortality. On the basis of trial sequential analysis, our results suggest no evidence of even a 5-10% relative risk (RR) increase of cancer and cancer-related deaths with any individual class of antihypertensive drugs studied. However, for the ACEi and ARB combination, the cumulative Z curve crossed the trial sequential monitoring boundary, suggesting firm evidence for at least a 10% RR increase in cancer risk. INTERPRETATION: Our analysis refutes a 5.0-10.0% relative increase in the risk of cancer or cancer-related death with the use of ARBs, ACEi, beta blockers, diuretics, and CCBs. However, increased risk of cancer with the combination of ACEi and ARBs cannot be ruled out. FUNDING: None

BACKGROUND: Recently concluded multicenter studies have shown that none of an array of echocardiographic indicators of ventricular dyssynchrony have enough sensitivity and specificity for predicting response to cardiac resynchronization therapy (CRT). Inotropic contractile reserve (ICR) on dobutamine stress echocardiography can differentiate viable myocardium from scar and is a predictor of improvement in regional and global left ventricular function in patients with cardiomyopathy. Its role in patients undergoing CRT is unknown. The aim of this study was to evaluate the role of ICR in predicting response to CRT in patients with markedly remodeled left ventricles. METHODS: Fifty-four patients (mean age, 69+/-11 years; 63% men) referred for clinically indicated CRT were evaluated. All patients underwent low-dose dobutamine stress echocardiography to assess for ICR, defined as an improvement in contractility in more than five of 16 left ventricular segments. RESULTS: During a mean follow-up period of 206+/-167 days, 31 patients (57%) were responders, as defined by a 5-point increase in ejection fraction after CRT. The presence of ICR was a stronger predictor of response to CRT (area under the curve, 0.94; chi2=39.0; P<.0001) compared with dyssynchrony (area under the curve, 0.74; chi2=10.07; P=.002). It was a significant predictor of response (odds ratio, 2.84; 95% confidence interval, 1.59 to 5.09; P<.0001), even after controlling for the other predictors, and provided incremental prognostic value beyond that provided by QRS duration and dyssynchrony (increase in area under the curve from 0.47 to 0.75 to 0.93; P=.030 and P=.008). CONCLUSIONS: In patients referred for CRT, ICR was a stronger predictor of response and provided incremental value beyond that of current known predictors of response to CRT (dyssynchrony and QRS duration). Dobutamine stress echocardiography may have an important role in identifying CRT responders, and further multicenter studies are needed to confirm this

Background: Intravenous (IV) Beta-blockade is currently not routinely recommended in the early management of patients with acute coronary syndromes (ACS)-even for patients without obvious contraindications. We performed a systematic review of the medical literature to determine if early IV beta-blockade improves the risk of in-hospital ventricular tachyarrhythmias (ventricular tachycardia/fibrillation) in patients with ACS. Methods: The authors searched the PubMed and EMBASE databases for randomized controlled trials and controlled clinical trials from 1965 through 2009. Intervention included intravenous beta-blockers administered within 24 hours of presentation. The comparator included standard medical therapy and/or placebo. The outcome assessed was the risk of development of in-hospital ventricular tachyarrhythmias (both Vtach and Vfib) in the intervention groups versus the comparator groups. The methodological quality of the studies was assessed. In-hospital mortality rates were compared using a forest plot of relative risk (RR; 95% confidence interval [CI]) using a random effect model (Mantel-Haenszel) between beta-blockers and controls. Statistical analysis was done with Review Manager V5.0. Results: Thirteen studies (total N = 114,801) met the inclusion/ exclusion criteria. In-hospital development of ventricular tachycardia/ fibrillation was reduced 1.88% (7.46% Vs 5.58%) with IV beta-blockers, RR = 0.56 (95% CI, 0.46-0.68; p<0.01). Conclusions: This systematic review suggests a benefit with early use of IV beta-blockers in appropriate patients with ACS for preventing development of ventricular tachyarrhythmias. (Table Presented)

Background: Recent clinical trials suggest that in patients already on conventional heart failure therapy the addition of angiotensin receptor blockers (ARBs) or aldosterone antagonists (AA) are reasonable therapeutic options to further reduce the risk of cardiovascular events. However, whether one is preferable over the other is unknown. Methods: PUBMED, EMBASE,and CENTRAL were searched for randomized clinical trials (RCTs), of trials testing either an ARB or an AA in patients with heart failure and reduced systolic function who were on conventional heart failure therapy (including diuretics,beta blockers and angiotensin converting enzyme inhibitors (ACEi)) with follow-up of at least 6-months. Efficacy (death, cardiovascular (CV) death, myocardialinfarction, stroke, heart failure hospitalization, CV death or heart failure hospitalization) and safety (hyperkalemia, hypotension, renal failure) outcomes were compared. Results: We identified 12 RCTs involving 29,514 participants that satisfied our inclusion criteria. When compared with placebo (reference rate ratio 1), the addition of aldosterone antagonists reduced death from all causes (rate ratio (RR) = 0.80, 95% Credibility Interval (CrI)0.64-0.97), cardiovascular death (RR = 0.79; 95% CrI 0.65-0.94) and heart failure hospitalization (RR = 0.73; 95% CrI 0.56- 0.93) with no difference for other efficacy outcomes. In contrast, the addition of ARBs did not significantly reduce the rate of any of the efficacy outcomes when compared with placebo. Moreover, ARBs but not AA increased the rate of hyper- (Figure presented) hyperkalemia (138% increase), renal failure (126% increase) and hypotension (63% increase). Conclusions: In patients with heart failure and reduced systolic function on conventional medications including ACEi, the risk-benefit ratio favors AA over ARBs

Background: In patients post myocardial infarction and in those with established coronary artery disease (CAD), lower heart rate has been shown to improve long term cardiovascular prognosis. However, how low is low enough and the existence of J-curve relationship has not been proven. Methods: We evaluated 9602 patients, with CAD and a LDL cholesterol level <130 mg/dL, randomized to atorvastatin 80 mg vs. 10 mg, enrolled in the TNT trial. The post-baseline, time-dependent heart rate were categorized into 10 mm Hg increments. The primary outcome was a composite of death from coronary disease, nonfatal myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. Results: Among the 9602 patients, 886 (9.23%) experienced a primary outcome at 4.9 years (median) of follow-up. The relationship between heart rate and primary outcome followed a J-curve with increased event rates above and below the reference heart rate range, both unadjusted and adjusted (for baseline covariates, treatment effect and LDL levels). A time-dependent, non-linear, multivariate Cox proportional hazard (PH) model identified a nadir of 52.4 bpm where the event rate was lowest (Figure). Similar, non-linear relationship, with higher risk of events at lower heart rate was found for most of the secondary outcomes of all-cause mortality, CV mortality, nonfatal MI, or stroke. (Figure presented) Conclusions: In patients with CAD, a very low heart rate portends an increased risk of future cardiovascular events

AIM: In patients with coronary artery disease (CAD), a J-curve relationship has been reported between blood pressure (BP) and future cardiovascular events. However, this is controversial. The purpose of the study was to determine the relationship between on-treatment BP and cardiovascular outcomes in patients with CAD. METHODS AND RESULTS: We evaluated 10 001 patients with CAD and a low-density lipoprotein (LDL) cholesterol level <130 mg/dL, randomized to atorvastatin 80 vs. 10 mg, enrolled in the TNT trial. The post-baseline, time-dependent BPs [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] were categorized into 10 mmHg increments. The primary outcome was a composite of death from coronary disease, non-fatal myocardial infarction (MI), resuscitated cardiac arrest, and fatal or non-fatal stroke. Among the 10 001 patients, 982 (9.82%) experienced a primary outcome at 4.9 years (median) of follow-up. The relationship between SBP or DBP and primary outcome followed a J-curve with increased event rates above and below the reference BP range, both unadjusted and adjusted (for baseline covariates, treatment effect, and LDL levels). A time-dependent, non-linear, multivariate Cox proportional hazard model identified a nadir of 146.3/81.4 mmHg where the event rate was lowest. A similar non-linear relationship with a higher risk of events at lower pressures was found for most of the secondary outcomes of all-cause mortality, cardiovascular mortality, non-fatal MI, or angina. However, for the outcome of stroke, lower was better for SBP. CONCLUSION: In patients with CAD, a low BP (<110-120/<60-70 mmHg) portends an increased risk of future cardiovascular events (except stroke)