Faculty Bibliography

OBJECTIVES: To investigate the relative benefits of unfractionated heparin, low molecular weight heparin(LMWH), fondaparinux, and bivalirudin as treatment options for patients with ST segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). DESIGN: Mixed treatment comparison and direct comparison meta-analysis of randomized trials in the era of stents and P2Y12 inhibitors. DATA SOURCES AND STUDY SELECTION: A search of Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) for randomized trials comparing unfractionated heparin plus glycoprotein IIb/IIIa inhibitor(GpIIb/IIIa inhibitor), unfractionated heparin, bivalirudin, fondaparinux, or LMWH plus GpIIb/IIIa inhibitor for patients undergoing primary PCI. OUTCOMES: The primary efficacy outcome was short term (in hospital or within 30 days) major adverse cardiovascular event; the primary safety outcome was short term major bleeding. RESULTS: We identified 22 randomized trials that enrolled 22 434 patients. In the mixed treatment comparison models, when compared with unfractionated heparin plus GpIIb/IIIa inhibitor, unfractionated heparin was associated with a higher risk of major adverse cardiovascular events (relative risk 1.49 (95% confidence interval 1.21 to 1.84), as were bivalirudin (relative risk 1.34 (1.01 to 1.78)) and fondaparinux (1.78 (1.01 to 3.14)). LMWH plus GpIIb/IIIa inhibitor showed highest treatment efficacy, followed (in order) by unfractionated heparin plus GpIIb/IIIa inhibitor, bivalirudin, unfractionated heparin, and fondaparinux. Bivalirudin was associated with lower major bleeding risk compared with unfractionated heparin plus GpIIb/IIIa inhibitor (relative risk 0.47 (0.30 to 0.74)) or unfractionated heparin (0.58 (0.37 to 0.90)). Bivalirudin, followed by unfractionated heparin, LMWH plus GpIIb/IIIa inhibitor, unfractionated heparin plus GpIIb/IIIa inhibitor, and fondaparinux were the hierarchy for treatment safety. Results were similar in direct comparison meta-analyses: bivalirudin was associated with a 39%, 44%, and 65% higher risk of myocardial infarction, urgent revascularization, and stent thrombosis respectively when compared with unfractionated heparin with or without GpIIb/IIIa inhibitor. However, bivalirudin was associated with a 48% lower risk of major bleeding compared with unfractionated heparin plus GpIIb/IIIa inhibitor and 32% lower compared with unfractionated heparin alone. CONCLUSIONS: In patients undergoing primary PCI, unfractionated heparin plus GpIIb/IIIa inhibitor and LMWH plus GpIIb/IIIa inhibitor were most efficacious, with the lowest rate of major adverse cardiovascular events, whereas bivalirudin was safest, with the lowest bleeding. These relationships should be considered in selecting anticoagulant therapies in patients undergoing primary PCI.

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.

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.

BACKGROUND: The long-term efficacy of beta-blockers in patients with and without myocardial infarction (MI) is controversial. METHODS AND RESULTS: This is post hoc analysis from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial of 4772 patients with prior MI, 7804 patients with known atherothrombosis, and 2101 patients with risk factors alone but without heart failure. Primary outcome was a composite of nonfatal MI, stroke, or cardiovascular mortality. The cohorts were divided into 2 groups based on baseline beta-blocker use. In the propensity score-matched prior MI cohort, after 28 months of follow-up, beta-blocker use was associated with a 31% lower risk of the primary outcome (70 [7.1%] versus 100 [10.2%]; hazards ratio, 0.69; 95% confidence interval, 0.50-0.94; P=0.021), driven by a lower risk of recurrent MI (33 [3.4%] versus 48 [4.9%]; hazards ratio, 0.62; 95% confidence interval, 0.39-1.00; P=0.049) with no difference in mortality (52 [5.3%] versus 66 [6.7%]; P=0.20). In the known atherothrombotic disease and the risk factors alone cohorts, beta-blocker use was not associated with lower ischemic outcomes, whereas a trend toward a higher risk of stroke (3.5% versus 1.5%; hazards ratio, 2.13; 95% confidence interval, 0.92-4.92; P=0.079) was observed in the risk factors alone cohort. This higher stroke risk was significant in the regression model adjusted to the propensity score (hazards ratio, 2.69; 95% confidence interval, 1.33-5.44; P=0.006) and in the multivariable models. CONCLUSIONSBeta: -blocker use in patients with prior MI but no heart failure was associated with a lower composite cardiovascular outcome driven by lower risk of recurrent MI with no difference in mortality. However, beta-blocker use was not associated with lower cardiovascular events in those without MI, with a suggestion of inferior outcome with regard to stroke risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00050817.

Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled hypertension despite the use of >/=3 antihypertensive medication classes or controlled hypertension while treated with >/=4 antihypertensive medication classes. Although a high prevalence of aTRH has been reported, few data are available on its association with cardiovascular and renal outcomes. We analyzed data on 14 684 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants to determine the association between aTRH (n=1870) with coronary heart disease, stroke, all-cause mortality, heart failure, peripheral artery disease, and end-stage renal disease. We defined aTRH as blood pressure not at goal (systolic/diastolic blood pressure >/=140/90 mm Hg) while taking >/=3 classes of antihypertensive medication or taking >/=4 classes of antihypertensive medication with blood pressure at goal during the year 2 ALLHAT study visit (1996-2000). Use of a diuretic was not required to meet the definition of aTRH. Follow-up occurred through 2002. The multivariable adjusted hazard ratios (95% confidence intervals) comparing participants with versus without aTRH were as follows: coronary heart disease (1.44 [1.18-1.76]), stroke (1.57 [1.18-2.08]), all-cause mortality (1.30 [1.11-1.52]), heart failure (1.88 [1.52-2.34]), peripheral artery disease (1.23 [0.85-1.79]), and end-stage renal disease (1.95 [1.11-3.41]). aTRH was also associated with the pooled outcomes of combined coronary heart disease (hazard ratio, 1.47; 95% confidence interval, 1.26-1.71) and combined cardiovascular disease (hazard ratio, 1.46; 95% confidence interval, 1.29-1.64). These results demonstrate that aTRH increases the risk for cardiovascular disease and end-stage renal disease. Studies are needed to identify approaches to prevent aTRH and reduce risk for adverse outcomes among individuals with aTRH.

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: The 2014 Eighth Joint National Committee panel recommendations for management of high blood pressure (BP) recommend a systolic BP threshold for initiation of drug therapy and a therapeutic target of <150 mm Hg in those >/=60 years of age, a departure from prior recommendations of <140 mm Hg. However, it is not known whether this is an optimal choice, especially for the large population with coronary artery disease (CAD). OBJECTIVES: This study sought to evaluate optimal BP in patients >/=60 years of age. METHODS: Patients 60 years of age or older with CAD and baseline systolic BP >150 mm Hg randomized to a treatment strategy on the basis of either atenolol/hydrochlorothiazide or verapamil-SR (sustained release)/trandolapril in INVEST (INternational VErapamil SR Trandolapril STudy) were categorized into 3 groups on the basis of achieved on-treatment systolic BP: group 1, <140 mm Hg; group 2, 140 to <150 mm Hg; and group 3, >/=150 mm Hg. Primary outcome was first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke. Secondary outcomes were all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, nonfatal stroke, heart failure, or revascularization, tabulated separately. Outcomes for each group were compared in unadjusted and multiple propensity score-adjusted models. RESULTS: Among 8,354 patients included in this analysis with an accumulated 22,308 patient-years of follow-up, 4,787 (57%) achieved systolic BP of <140 mm Hg (group 1), 1,747 (21%) achieved systolic BP of 140 to <150 mm Hg (group 2), and 1,820 (22%) achieved systolic BP of >/=150 mm Hg (group 3). In unadjusted models, group 1 had the lowest rates of the primary outcome (9.36% vs. 12.71% vs. 21.32%; p < 0.0001), all-cause mortality (7.92% vs. 10.07% vs. 16.81%; p < 0.0001), cardiovascular mortality (3.26% vs. 4.58% vs. 7.80%; p < 0.0001), MI (1.07% vs. 1.03% vs. 2.91%; p < 0.0001), total stroke (1.19% vs. 2.63% vs. 3.85%; p <0.0001), and nonfatal stroke (0.86% vs 1.89% vs 2.86%; p<0.0001) compared with groups 2 and 3, respectively. In multiple propensity score-adjusted models, compared with the reference group of <140 mm Hg (group 1), the risk of cardiovascular mortality (adjusted hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.01 to 1.77; p = 0.04), total stroke (adjusted HR: 1.89; 95% CI: 1.26 to 2.82; p = 0.002) and nonfatal stroke (adjusted HR: 1.70; 95% CI: 1.06 to 2.72; p = 0.03) was increased in the group with BP of 140 to <150 mm Hg, whereas the risk of primary outcome, all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, and nonfatal stroke was increased in the group with BP >/=150 mm Hg. CONCLUSIONS: In hypertensive patients with CAD who are >/=60 years of age, achieving a BP target of 140 to <150 mm Hg as recommended by the JNC-8 panel was associated with less benefit than the previously recommended target of <140 mm Hg.