Faculty Bibliography

Previous studies have debated the notion that low blood pressure (BP) during treatment, particularly diastolic (DBP), is associated with increased risk of cardiovascular disease. We evaluated the impact of low BP on cardiovascular outcomes in a high-risk population of 15,244 hypertensive patients, almost half of whom had a history of coronary artery disease (CAD). In the prospective Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, patients were randomized to valsartan or amlodipine regimens and followed for 4.2 years (mean) with no difference in the primary cardiovascular endpoint. A Cox proportional hazards model was used to evaluate the relationship between average on-treatment BP and clinical outcomes. The relationship between BP and cardiovascular events was adjusted for age, gender and body mass index, and baseline qualifying risk factors and diseases (smoking, high total cholesterol, diabetes mellitus, proteinuria, CAD, previous stroke and left ventricular hypertrophy). DBP >/= 90 mmHg, compared with < 90 mmHg, was associated with increased incidence of the primary cardiovascular endpoint (all cardiac events); however, DBP < 70 mmHg, compared with >/= 70 mmHg, was not associated with increased incidence after covariate adjustment (no J-shaped curve). Similar results were observed for death, myocardial infarction (MI), heart failure and stroke, considered separately. Nadir for MI was at DBP of 76 mmHg and for stroke 60 mmHg. The ratio of MI to stroke increased with lower DBP. In CAD patients the MI to stroke ratio was more pronounced than in patients without CAD but there was no significant J-curve in either group. Systolic BP >/= 150 but not < 130 mmHg, compared with 130-149 mmHg, similarly was associated with increased risk for primary outcome. In conclusion, patients in BP strata >/= 150/90 mmHg, but not patients in BP strata < 130/70 mmHg, were at increased risk for adverse outcomes in this hypertensive, high-risk population. Although benefit in preventing MI in relation to preventing stroke levels off for the lowest BPs, these data provide no support for a J-curve in the treatment of high-risk hypertensive patients . The increase in the ratio of MI to stroke with lower DBP indicates target organ heterogeneity in that the optimal on-treatment DBP for cerebroprotection is below that for cardioprotection.

BACKGROUND: Transradial access for cardiac catheterisation results in lower bleeding and vascular complications than the traditional transfemoral access route. However, the increased radiation exposure potentially associated with transradial access is a possible drawback of this method. Whether transradial access is associated with a clinically significant increase in radiation exposure that outweighs its benefits is unclear. Our aim was therefore to compare radiation exposure between transradial access and transfemoral access for diagnostic coronary angiograms and percutaneous coronary interventions (PCI). METHODS: We did a systematic review and meta-analysis of the scientific literature by searching the PubMed, Embase, and Cochrane Library databases with relevant terms, and cross-referencing relevant articles for randomised controlled trials (RCTs) that compared radiation parameters in relation to access site, published from Jan 1, 1989, to June 3, 2014. Three investigators independently sorted the potentially relevant studies, and two others extracted data. We focused on the primary radiation outcomes of fluoroscopy time and kerma-area product, and used meta-regression to assess the changes over time. Secondary outcomes were operator radiation exposure and procedural time. We used both fixed-effects and random-effects models with inverse variance weighting for the main analyses, and we did confirmatory analyses for observational studies. FINDINGS: Of 1252 records identified, we obtained data from 24 published RCTs for 19 328 patients. Our primary analyses showed that transradial access was associated with a small but significant increase in fluoroscopy time for diagnostic coronary angiograms (weighted mean difference [WMD], fixed effect: 1.04 min, 95% CI 0.84-1.24; p<0.0001) and PCI (1.15 min, 95% CI 0.96-1.33; p<0.0001), compared with transfemoral access. Transradial access was also associated with higher kerma-area product for diagnostic coronary angiograms (WMD, fixed effect: 1.72 Gy.cm2, 95% CI -0.10 to 3.55; p=0.06), and significantly higher kerma-area product for PCI (0.55 Gy.cm2, 95% CI 0.08-1.02; p=0.02). Mean operator radiation doses for PCI with basic protection were 107 muSv (SD 110) with transradial access and 74 muSv (68) with transfemoral access; with supplementary protection, the doses decreased to 21 muSv (17) with transradial access and 46 muSv (9) with transfemoral. Meta-regression analysis showed that the overall difference in fluoroscopy time between the two procedures has decreased significantly by 75% over the past 20 years from 2 min in 1996 to about 30 s in 2014 (p<0.0001). In observational studies, differences and effect sizes remained consistent with RCTs. INTERPRETATION: Transradial access was associated with a small but significant increase in radiation exposure in both diagnostic and interventional procedures compared with transfemoral access. Since differences in radiation exposure narrow over time, the clinical significance of this small increase is uncertain and is unlikely to outweigh the clinical benefits of transradial access. FUNDING: None.

INTRODUCTION: Women with acute myocardial infarction are treated less aggressively than men and have a higher mortality. It is possible that these sex-related differences in outcome are a result of differences in baseline risk and management. METHODS AND RESULTS: We undertook a meta-analysis to study the differences in mortality among women and men with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (P-PCI). Studies reporting sex-specific crude mortality rates and/or adjusted effect estimates in STEMI patients undergoing P-PCI were identified. Among 48 studies, involving 103,895 patients, (26,556 women and 77,337 men), the crude in-hospital [pooled relative risk (RR): 1.94, 95% confidence interval (CI): 1.74-2.16, p<0.001; 23 studies (n=43,872)], 30-day [RR: 1.76, 95% CI: 1.50-2.07, p<0.001; 20 studies (n=43,279)], and long-term [RR: 1.60, 95% CI: 1.46-1.76, p<0.001; 26 studies (n=51,656)] mortality was significantly higher in women compared to men. When meta-analysis using adjusted effect estimates from individual studies was performed, in-hospital [RR: 1.31, 95% CI: 1.08-1.65, p=0.007; 14 studies (n=33,380)] and 30-day mortality [RR: 1.19, 95% CI: 1.01-1.39, p=0.03; 14 studies (n=28,564)] remained significant while long-term mortality [RR: 1.01, 95% CI: 0.93-1.11, p=0.75; 20 studies (n=52,492)] was no longer different between women and men. CONCLUSIONS: Sex-based differences exist in short and long-term mortality among patients with STEMI undergoing P-PCI. However, these differences were markedly attenuated following adjustment for clinical differences and/or hospital course. Despite adjustment, short-term mortality remains higher in women than men, while long-term mortality was no longer significantly different.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACEi) are widely used in the treatment of patients with hypertension. However, their efficacy in hypertensive blacks when compared with other antihypertensive agents is not well established. METHODS: Cohort study of patients using data from a clinical data warehouse of 434,646 patients from New York City's Health and Hospitals Corporation (HHC) from January 2004 - December 2009. Patients were divided into the following comparison groups: ACEi vs. Calcium Channel Blocker (CCB); ACEi vs. thiazide diuretics and ACEi vs. beta-blockers. Primary outcome was a composite of death, myocardial infarction or stroke. Secondary outcomes include the individual components and heart failure. RESULTS: In the propensity score matched ACEi vs. CCB comparison cohort (4,506 blacks in each group), ACEi was associated with higher risk of primary outcome (HR=1.45; 95% CI 1.19, 1.77; P=0.0003), myocardial infarction (HR=3.40; 95% CI 1.25, 9.22; P=0.02), stroke (HR=1.82; 95% CI 1.29, 2.57; P=0.001) and heart failure (HR=1.77; 95% CI 1.30, 2.42; P=0.0003) when compared with CCB. For the ACEi vs. thiazide diuretics comparison (5,337 blacks in each group), ACEi was associated with higher risk of primary outcome (HR=1.65; 95% CI 1.33, 2.05; P<0.0001), death (HR=1.35; 95% CI 1.03, 1.76; P=0.03), myocardial infarction (HR=4.00; 95% CI 1.34, 11.96; P=0.01), stroke (HR=1.97; 95% CI 1.34, 2.92; P=0.001) and heart failure (HR=3.00; 95% CI 1.99, 4.54; P<0.0001). For the ACEi vs. beta-blocker comparison, the outcomes between the groups were not significantly different. CONCLUSIONS: In a real-world cohort of hypertensive blacks, ACEi was associated with higher risk of cardiovascular events when compared with CCB or thiazide diuretics.

INTRODUCTION: Perflutren microbubble/microsphere ultrasound contrast agents have a black-box warning based on case reports of serious cardiopulmonary events. There have been several subsequent observational safety studies. Large spontaneous reporting databases may help detect/refine signals of rare adverse events that elude other data sources/study designs. OBJECTIVE: The objective of this study was to supplement existing knowledge of the reported safety of perflutren using statistical analysis of spontaneous reports. METHODS: We analyzed information from the US Food and Drug Administration Adverse Event Reporting System using a disproportionality analysis. Analysis of overall reporting for perflutren was supplemented by subset (age, indication) analysis. A signal of disproportionate reporting (SDR) was defined as EB05 >2. RESULTS: Overall, 18/380 Preferred Terms and 1/83 Standardized Medical Queries had SDRs. Most were small (EB05 = 2-4). Back pain and flank pain were the largest SDRs followed by events compatible with signs/symptoms of hypersensitivity. The general pattern of SDRs in the subset analysis was consistent with the overall analysis. Almost all events with SDRs were literally or conceptually labeled. Except for chest pain (higher in the age <65 years subgroup) and back pain (higher in the age >/=65 years subgroup), there were no statistically significant differences between age subsets. Except for the Preferred Terms Pruritus and Urticaria and the narrow Standardized Medical Queries Ventricular tachyarrhythmia, Angioedema, Oropharyngeal allergic conditions, and Hypersensitivity (higher in the stress test subgroup), there were no statistically significant reporting differences between indication subsets. There were no SDRs associated with the major cardiovascular events of death, myocardial infarction/ischemia, angina, arrhythmias, or convulsions in any analysis. CONCLUSIONS: Our combined signal detection/evaluation analysis did not identify SDRs of novel adverse events or major cardiovascular events associated with perflutren ultrasound contrast agents. The negative results for major cardiovascular events extend previous signal evaluation exercises supporting the relative cardiovascular safety of these agents.

BACKGROUND: Concordance with the Dietary Approaches to Stop Hypertension (DASH) diet has been shown to reduce blood pressure (BP) in short-term intervention studies, but long-term effects are unclear. We evaluated the association of DASH diet concordance with BP trajectories and incidence of hypertension, in 2187 men and women (mean age 52.5 years at baseline) participating in the Framingham Offspring cohort. METHOD: Diet and BP were assessed from 1991 to 2008, with a median follow-up time of 13.4 years. DASH scores (ranging from 0 for worst to 10 for best concordance with DASH diet) were calculated by summing 10 food components that comprise the DASH diet pattern, including fruits and vegetables, low-fat dairy products, lean meat, and plant-based protein. Mixed-effect and Cox regression models were applied, to assess the association of DASH diet concordance with BP longitudinal change and with incidence of hypertension, respectively. All analyses were adjusted for age, sex, smoking status, history of diabetes, BMI, and physical activity. RESULT: Overall, SBP increased by 0.34 mmHg and DBP by 0.10 mmHg annually, in the Framingham Offspring cohort. Every unit increase in the DASH score resulted in a modest increase in SBP of 0.054 mmHg/year (P = 0.028). No associations were observed between DASH diet concordance and DBP or incidence of hypertension. CONCLUSION: Long-term concordance with the DASH diet was not associated with a decreasing BP trajectory over time, or with decreased incidence of hypertension, in this population of middle-aged adults.

BACKGROUND: The choice of drug-eluting stent in the treatment of patients with diabetes mellitus and coronary artery disease who are undergoing percutaneous coronary intervention (PCI) has been debated. Previous studies comparing paclitaxel-eluting stents with stents eluting rapamycin (now called sirolimus) or its analogues (everolimus or zotarolimus) have produced contradictory results, ranging from equivalence between stent types to superiority of everolimus-eluting stents. METHODS: We randomly assigned 1830 patients with diabetes mellitus and coronary artery disease who were undergoing PCI to receive either a paclitaxel-eluting stent or an everolimus-eluting stent. We used a noninferiority trial design with a noninferiority margin of 4 percentage points for the upper boundary of the 95% confidence interval of the risk difference. The primary end point was target-vessel failure, which was defined as a composite of cardiac death, target-vessel myocardial infarction, or ischemia-driven target-vessel revascularization at the 1-year follow-up. RESULTS: At 1 year, paclitaxel-eluting stents did not meet the criterion for noninferiority to everolimus-eluting stents with respect to the primary end point (rate of target-vessel failure, 5.6% vs. 2.9%; risk difference, 2.7 percentage points [95% confidence interval, 0.8 to 4.5]; relative risk, 1.89 [95% confidence interval, 1.20 to 2.99]; P=0.38 for noninferiority). There was a significantly higher 1-year rate in the paclitaxel-eluting stent group than in the everolimus-eluting stent group of target-vessel failure (P=0.005), spontaneous myocardial infarction (3.2% vs. 1.2%, P=0.004), stent thrombosis (2.1% vs. 0.4%, P=0.002), target-vessel revascularization (3.4% vs. 1.2%, P=0.002), and target-lesion revascularization (3.4% vs. 1.2%, P=0.002). CONCLUSIONS: In patients with diabetes mellitus and coronary artery disease undergoing PCI, paclitaxel-eluting stents were not shown to be noninferior to everolimus-eluting stents, and they resulted in higher rates of target-vessel failure, myocardial infarction, stent thrombosis, and target-vessel revascularization at 1 year. (Funded by Boston Scientific; TUXEDO-India Clinical Trials Registry-India number, CTRI/2011/06/001830).