Faculty Bibliography

BACKGROUND: Increasingly, apparent treatment-resistant hypertension has been recognized. However, much of the prevalence, predictors, and outcomes are largely unknown, especially in patients with coronary artery disease. METHODS: We evaluated 10,001 patients with coronary artery disease who were enrolled in the Treating to New Targets trial. Apparent treatment-resistant hypertension was defined as blood pressure >/=140 mm Hg despite 3 antihypertensive agents or <140 mm Hg with >/=4 antihypertensive agents. The primary outcome was major cardiovascular events (composite of fatal coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, and stroke). RESULTS: Among the 10,001 patients in the trial, 1112 (11.1%) had apparent treatment-resistant hypertension. In a multivariable model adjusting for baseline differences, the treatment-resistant hypertension group had a 64% increase in primary outcome (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.39-1.94; P < .001), driven by a 69% increase in coronary heart disease death (HR, 1.69; 95% CI, 1.22, 2.34; P = .001) and 73% increase in nonfatal myocardial infarction (HR, 1.73; 95% CI, 1.39-2.16, P < .0001) when compared with the no apparent treatment-resistant hypertension group. In addition, patients with apparent treatment-resistant hypertension had a 71% increase in major coronary event (P < .0001), 45% increase in death (P = .001), 33% increase in heart failure (P = .05), 53% increase in any cardiovascular event (P < .0001), 60% increase in any coronary event (P < .0001), 68% increase in angina (P < .0001), and 51% increase in coronary revascularization (P < .0001) when compared with the no apparent treatment-resistant hypertension group. Results were largely similar whether the definition of apparent treatment-resistant hypertension was based on a blood pressure >/=140 mm Hg despite 3 agents or a blood pressure <140 mm Hg with >/=4 agents. CONCLUSIONS: In patients with coronary artery disease, apparent treatment-resistant hypertension is associated with a marked increase in the risk of cardiovascular morbidity and mortality, including an increase in all-cause death.

Objective: Current national guidelines include category 1 recommendations for perioperative chemotherapy or adjuvant chemoradiation with surgical resection for patients with stage IB-IIIB gastric cancer. We conducted a meta-analysis of randomized trials in which chemotherapy was prospectively tested against chemoradiation with surgical resection. Methods: We electronically searched PubMed and EMBASE for randomized, controlled clinical trials involving patients with gastric adenocarcinoma, status post-R0 resection. The interventions compared were adjuvant chemotherapy versus chemoradiation, with any chemotherapy regimen. The primary outcomes of interest were disease-free survival and overall survival. The Mantel-Haenszel random-effects model was used to calculate effect sizes. Results: Six trials that included 1,171 patients were evaluated; 599 were randomized to adjuvant chemoradiation and 572 to chemotherapy alone. Chemoradiation was associated with a significant increase in disease-free survival (odds ratio 1.48, 95% confidence interval 1.08-2.03) when compared to chemotherapy alone. However, there was no significant difference in overall survival (odds ratio 1.27, 95% confidence interval 0.95-1.71). Five trials found no statistically significant differences in toxicities between the two groups. Conclusion: In patients with gastric cancer status post-R0 resection, adjuvant chemoradiation was associated with higher disease-free survival when compared to chemotherapy alone. It remains appropriate to design trials testing new systemic agents with radiotherapy. (c) 2014 S. Karger AG, Basel.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are highly effective at improving prognosis in a variety of disease states such as hypertension, cardiovascular disease, systolic heart failure, and acute coronary syndrome. Although these medications have been used in clinical practice for decades, not all ACE inhibitors are equal, as agents within this class vary in lipophilicity, tissue-ACE binding, antioxidant properties, antiinflammatory properties, bradykinin site selectivity, and duration of action. The objective of this systematic review and metaanalysis was to evaluate the effects of perindopril vs enalapril on left ventricular function in patients with systolic heart failure. METHODS: We conducted a systematic review and metaanalysis of trials comparing perindopril and enalapril in systolic heart failure. Relevant studies were identified through searches of MEDLINE, EMBASE, Web of Science, and Google Scholar. RESULTS: Three trials comparing enalapril with perindopril in 116 patients with systolic heart failure were identified. Compared to enalapril, perindopril significantly improved cardiac sympathetic nerve activity: the pooled mean net change in heart to mediastinum ratio was 0.12 (95% confidence interval [CI]: 0.08, 0.16) and the pooled mean net change in washout rate was -3.51% (95% CI: -4.17, -2.85). Other variables also showed improvement. The pooled mean net change in New York Heart Association functional class was -0.44 (95% CI: -0.86, -0.03) and the change in brain natriuretic peptide was -64.1 [95% CI: -80.8, -47.4]. The change in left ventricular ejection fraction was not significantly greater with perindopril than enalapril: 1.15% (95% CI: -2.74, 5.04). However, in the 2 trials that switched patients from enalapril to perindopril, left ventricular ejection fraction at 6 months was significantly greater in the perindopril group: 2.41% (95% CI: 1.26, 3.55; P<0.0001). CONCLUSION: In patients with systolic heart failure, perindopril significantly improves cardiac sympathetic nerve activity, brain natriuretic peptide, and New York Heart Association functional class compared to enalapril. Additionally, when patients were switched from enalapril to perindopril, left ventricular ejection fraction at 6 months was significantly greater.

BACKGROUND: Cilostazol overcomes high on-treatment platelet reactivity (HTPR) and reduces adverse cardiovascular (CV) outcomes after percutaneous coronary intervention (PCI). However, the role for triple antiplatelet therapy (TAPT) with cilostazol in addition to aspirin and clopidogrel after PCI is not well defined. METHODS: We conducted a MEDLINE/EMBASE/CENTRAL search for randomised trials, until May 2014, evaluating TAPT compared with dual antiplatelet therapy (DAPT) of aspirin and clopidogrel alone in patients undergoing PCI and reporting platelet reactivity and/or CV outcomes. The primary platelet reactivity outcome was differences in platelet reactivity unit (PRU) with secondary outcomes of %platelet inhibition and rate of HTPR. The primary CV outcome was major adverse cardiovascular events (MACE), with secondary outcomes of death, cardiovascular death, myocardial infarction, stent thrombosis (ST), target lesion revascularisation (TLR) and target vessel revascularisation (TVR) as well as safety outcomes of bleeding and drug discontinuations. RESULTS: In 17 trials that evaluated platelet reactivity outcomes, the mean PRU value was 47.73 units lower with TAPT versus DAPT (95% CI -61.41 to -34.04, p<0.0001; mean PRU 182.90 vs 232.65). TAPT also increased platelet inhibition by 12.71% (95% CI 10.76 to 14.67, p<0.0001), and led to a 60% reduction in the risk of HTPR (relative risk=0.40; 95% CI 0.30 to 0.53) compared with DAPT. Moreover, among the 34 trials that evaluated CV outcomes, TAPT reduced the risk of MACE (incident rate ratio (IRR)=0.68; 95% CI 0.60 to 0.78), TLR (IRR=0.57; 95% CI 0.44 to 0.73), TVR (IRR=0.69; 95% CI 0.59 to 0.81) and ST (IRR=0.63; 95% CI 0.40 to 0.98) with no difference for other outcomes including bleeding, even in trials using drug-eluting stents. Drug discontinuation due to adverse effects was, however, higher with TAPT vs DAPT (IRR=1.59; 95% CI 1.32 to 1.91). CONCLUSIONS: In patients undergoing PCI, addition of cilostazol to DAPT results in decreased platelet reactivity and a significant reduction in CV outcomes including ST, even in the drug-eluting stent era.

Objective. Negative results of recent randomized clinical trials testing the hypothesis of target therapy for patients with high on-treatment platelet reactivity (HOPR) have questioned its independent impact on clinical outcomes. 26 studies with 28.178 patients were included, with a median age of 66.8 (64-68) and 22.7% (22.4-27.8), of female gender. After a median follow-up of 1 year (0.1-1), cardiac adverse events occurred in 8.3% (3-11; all results are reported as median and interquartile range) of patients. Pooling all studies together, on-treatment platelet reactivity significantly increased the risk of adverse events (OR 1.33 [1.09, 1.64], I 2 = 0%). However, a sensitivity analysis showed that HOPR did not increase the risk of adverse events for patients with ACS, AMI, or stable angina as well as patients resistant to aspirin, ADP antagonists, or both. For all studies, publication bias was formally evident; after adjusting for this, HOPR did not significantly increase adverse cardiac events (OR 1.1 : 0.89-1.22, I 2 0%). Conclusions. After adjusting for clinical confounders (like risk factors and clinical presentation) and for relevant publication bias, HOPR was not an independent prognostic indicator in unselected patients with both stable and unstable coronary disease for an adverse cardiac event. The clinical importance of HOPR for high-risk populations remains to be assessed.

OBJECTIVE: To assess long-term outcomes of Endeavor Zotarolimus-eluting stent (E-ZES) implantation in patients with diabetes mellitus (DM). Background: Patients with DM and coronary artery disease have lower restenosis with drug-eluting stent (DES) compared with bare-metal stents. Recent data suggest that the E-ZES is inferior to other DES in this population. METHODS: Patient-level data for 601 patients with DM from the ENDEAVOR III and ENDEAVOR IV trials were pooled, of which 337 were treated with E-ZES and 264 were treated with other DES. The primary outcome was target vessel failure (TVF) in the course of 5 years. Outcomes are reported as rates using Kaplan-Meier (KM) survival method and differences between E-ZES and other stent types (sirolimus-eluting stent or paclitaxel-eluting stent) were compared using the log-rank statistic. The independent effect of stent type on TVF was assessed using Cox proportional hazards regression. RESULTS: Baseline characteristics were similar between the groups. Five-year TVF KM rate estimate was numerically lower for E-ZES, but the difference did not reach statistical significance (20.2 vs. 26.9%, P = 0.065). The 5-year KM rate estimates of major adverse cardiac events (17.7 vs. 26.6%, P = 0.012), death (7.6 vs. 15.0%, P = 0.004), and myocardial infarction (1.3 vs. 5.1%, P = 0.011) were also lower for E-ZES versus other DES. Conclusions: Patients with DM implanted with E-ZES have favorable long-term outcomes compared to first-generation DES. Long-term performance of DES should be assessed routinely and may differ from initial performance. (c) 2013 Wiley Periodicals, Inc.

OBJECTIVE: Limited studies suggest that blood pressure variability over time is a risk factor of long-term cardiovascular outcomes. However, most of these were in populations with pre-existing cardiovascular diseases (CVD) and studies in general population are lacking. METHODS: The study included 11,153 participants in a population-based, prospective cohort study in Araihazar, Bangladesh. Resting blood pressure was measured at baseline and every two years thereafter. Participants were followed up for an average of 6.5years (2002-2009). RESULTS: Male gender, older age, baseline systolic blood pressure (SBP), and absence of betel leaf use were independently positively associated with greater SBP variability over time. There was a significant association between SBP variability and the risk of death from overall CVD, especially from major CVD events. The positive association with the risk of death from any cause and stroke in age- and sex-adjusted models was attenuated in fully-adjusted models. In addition, the hazard ratio (HR) of stroke mortality was greater for individuals with both high baseline and high SBP variability. Similar patterns of HRs were observed for all-cause and CVD mortalities. CONCLUSION: In this rural Bangladeshi population, variability in SBP contributes to the risk of death from CVD and may further potentiate the increased mortality risk associated with high SBP.

BACKGROUND: In randomized clinical trials, procedural myocardial infarction (MI) or spontaneous MI is often weighted equally as a component of a composite clinical end point. An underlying assumption of this approach is that procedural and spontaneous MIs have similar prognostic impact. Our aim was to evaluate the prognostic impact of procedural vs spontaneous MI in patients undergoing percutaneous coronary intervention (PCI). METHODS: We used data from the EVENT registry to examine the relative prognostic impact of procedural vs spontaneous MI. For the purposes of this study, patients undergoing initial PCI were stratified into 3 groups-no MI, procedural MI, or spontaneous MI-based on standard definitions applied at the time of the index procedure and followed for 1 year for outcomes of all-cause mortality and cardiovascular mortality. Multiple propensity score adjustment analysis was used to adjust for differences in baseline covariates among the 3 groups. RESULTS: Among 7,380 patients included in this analysis, 4,568 (62%) patients had no MI, 580 (8%) patients had procedural MI at the time of their index procedure, and 2,232 (30%) patients presented with a spontaneous MI before PCI. In unadjusted analyses, there was a graded increase in risk of 1-year mortality (1.9% vs 3.1% vs 3.9%; P < .0001) and cardiovascular death (0.5% vs 1.0% vs 1.7%; P < .0001) across the 3 groups. After adjusting for propensity scores, spontaneous MI (adjusted hazard ratio [HR] 1.62, 95% CI 1.11-2.37, P = .01) but not procedural MI (adjusted HR 1.51, 95% CI 0.89-2.54, P = .12) was independently associated with death at 12 months when compared with the no-MI group. Findings were similar when the analysis was limited to cardiovascular death (adjusted HRs 3.14 [95% CI 1.68-5.90, P < .001] and 1.74 [95% CI 0.69-4.40, P = .24], respectively). CONCLUSIONS: Among patients undergoing PCI, spontaneous but not procedural MI was independently associated with death and cardiovascular death at 1 year. These finding suggest that the prognostic impact of procedural MI may be less than that of spontaneous MI and should be considered in designing end points for future studies of coronary revascularization.