Faculty Bibliography

BACKGROUND: Peripheral edema is a common adverse effect of calcium channel blockers. The addition of a renin-angiotensin system blocker, either an angiotensin-converting enzyme inhibitor or an ARB, has been shown to reduce peripheral edema in a dose-dependent way. METHODS: We performed a MEDLINE/COCHRANE search for all prospective randomized controlled trials in patients with hypertension, comparing calcium channel blocker monotherapy with calcium channel blocker/renin-angiotensin system blocker combination from 1980 to the present. Trials reporting the incidence of peripheral edema or withdrawal of patients because of edema and total sample size more than 100 were included in this analysis. RESULTS: We analyzed 25 randomized controlled trials with 17,206 patients (mean age 56 years, 55% were men) and a mean duration of 9.2 weeks. The incidence of peripheral edema with calcium channel blocker/renin-angiotensin system blocker combination was 38% lower than that with calcium channel blocker monotherapy (P<.00001) (relative risk [RR] 0.62; 95% confidence interval [CI], 0.53-0.74). Similarly, the risk of withdrawal due to peripheral edema was 62% lower with calcium channel blocker/renin-angiotensin system blocker combination compared with calcium channel blocker monotherapy (P=.002) (RR 0.38; 95% CI, 0.22-0.66). ACE inhibitors were significantly more efficacious than ARBs in reducing the incidence of peripheral edema (P<.0001) (ratio of RR 0.74; 95% CI, 0.64-0.84) (indirect comparison). CONCLUSION: In patients with hypertension, the calcium channel blocker/renin-angiotensin system blocker combination reduces the risk of calcium channel blocker-associated peripheral edema when compared with calcium channel blocker monotherapy. ACE inhibitor seems to be more efficacious than ARB in reducing calcium channel blocker-associated peripheral edema, but head-to-head comparison studies are needed to prove this

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

Cardiac resynchronization therapy (CRT) increases cardiac performance in patients with heart failure, but its effect on arterial pressure is not well established. To determine the effect of CRT on systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) a systematic review using standard nomenclatures for CRT was done in Scopus (MEDLINE and Embase), Cochrane Controlled Trials Register, National Institutes of Health http://www.ClinicalTrials.gov database, and bibliography of select meta-analyses for studies evaluating CRT in patients with dilated cardiomyopathy. Two independent investigators extracted the articles based on predefined criteria. The primary outcome was difference in arterial pressure parameters from baseline to after CRT in nonrandomized cohort trials. This was then validated by comparing the change in arterial pressure between CRT and medical therapy groups in randomized controlled trials. A random-effects model was used for analyses. Analyses of 15 nonrandomized studies showed that CRT resulted in an increase (from baseline) in SBP by 4.4 mm Hg (95% confidence interval [CI] 0.8 to 8.0, p = 0.02), no change in DBP (p = 0.21), and an increase in PP by 2.8 mm Hg (95% CI 1.0 to 4.6, p = 0.003). Results from the 3 randomized controlled trials were concordant with an increase in SBP by 3.9 mm Hg (95% CI 1.1 to 6.8, p = 0.007), no effect on DBP (p = 0.40), and an increase in PP by 4.3 mm Hg (95% CI 4.1 to 4.5, p <0.001) compared to medical therapy. In conclusion, CRT is associated with a modest increase in SBP and PP in patients with heart failure

BACKGROUND: Patients with human immunodeficiency virus (HIV) infection are at increased risk of accelerated coronary artery disease (CAD) and cardiovascular events. Stress echocardiography (SE) is routinely used for risk stratification and prognosis of patients with known or suspected CAD. The prognostic value of SE in this high-risk group is unknown. The purpose of this study was to evaluate the prognostic value of SE in HIV-infected patients with known or suspected CAD. METHODS AND RESULTS: We evaluated 311 patients (age, 52 +/- 9 years; 74% men; left ventricular ejection fraction, 54 +/- 12%) with history of HIV, undergoing SE (56% dobutamine). Left ventricular wall motion was evaluated on a 16-segment model, 5-point scale. An abnormal SE was defined by a fixed (infarction), biphasic, or new (ischemia) wall motion abnormality on stress. Follow-up for cardiac death and myocardial infarction was obtained. Seventy-nine (26%) patients had an abnormal SE. After 2.9 +/- 1.9 years, 17 confirmed myocardial infarction and 14 cardiac deaths occurred. SE risk-stratified patients into normal versus abnormal subgroups (event rate, 0.6% per year versus 11.8% per year; P < 0.0001). Both abnormal SE (hazard ratio, 28.2; 95% confidence interval, 6.2 to 128.0; P < 0.0001) and the presence of any ischemia on SE (hazard ratio, 3.4; 95% confidence interval, 1.3 to 8.6; P = 0.009) were independent predictors of cardiac events. On a forward conditional Cox proportional hazards regression model, SE provided incremental prognostic value over clinical, stress ECG, and resting echocardiographic variables (global chi(2) increased from 17.8 to 24.5 to 65 to 109, P < 0.05 across all groups). CONCLUSIONS: SE can effectively risk-stratify and prognosticate patients with HIV. The presence of ischemia and scar during SE provides independent and incremental prognostic value over traditional variables. A normal SE response portends a benign prognosis even in this high-risk subset

Hydrochlorothiazide (HCTZ) has become by far the most commonly prescribed antihypertensive drug in the US. In 2008, 47.8 million prescriptions were written for HCTZ alone and 87.1 million prescriptions for HCTZ combinations. However, there is no evidence that HCTZ in its usual dose of 12.5-25 mg daily reduces myocardial infarction, stroke, or death. In a meta-analysis of 19 randomized trials with over 1400 patients, the 24-hour decrease in blood pressure with HCTZ was inferior to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers (P <.001 for all). Even in combination with an angiotensin-converting enzyme inhibitor, HCTZ was found to reduce morbidity and mortality less well than a calcium channel blocker. As measured by the adherence rate, thiazides are less well tolerated than any other drug class. Because outcome data at the usual daily dose of 12.5-25 mg are lacking, antihypertensive efficacy is paltry, and adherence is poor, HCTZ is an inappropriate first-line drug in hypertension. If a 'thiazide-type' diuretic is indicated, either chlorthalidone or indapamide should be selected