Non-invasive assessment of low risk acute chest pain in the emergency department: A comparative meta-analysis of prospective studies.

BACKGROUND: The aim of this meta-analysis was to compare the diagnostic accuracy of cardiac computed tomographic angiography (CCTA), stress echocardiography (SE) and radionuclide single photon emission computed tomography (SPECT) for the assessment of chest pain in emergency department (ED) setting. METHODS: A systematic review of Medline, Cochrane and Embase was undertaken for prospective clinical studies assessing the diagnostic efficacy of CCTA, SE or SPECT, as compared to intracoronary angiography (ICA) or the later presence of major adverse clinical outcomes (MACE), in patients presenting to the ED with chest pain. Standard approach and bivariate analysis were performed. RESULTS: Thirty-seven studies (15 CCTA, 9 SE, 13 SPECT) comprising a total of 7800 patients fulfilled inclusion criteria. The respective weighted mean sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and total diagnostic accuracy for CCTA were: 95%, 99%, 84%, 100% and 99%, for SE were: 84%, 94%, 73%, 96% and 96%, and for SPECT were: 85%, 86%, 57%, 95% and 88%. There was no significant difference between modalities in terms of NPV. Bivariate analysis revealed that CCTA had statistically greater sensitivity, specificity, PPV and overall diagnostic accuracy when compared to SE and SPECT. CONCLUSIONS: All three modalities, when employed by an experienced clinician, are highly accurate. Each has its own strengths and limitations making each well suited for different patient groups. CCTA has higher accuracy than SE and SPECT, but it has many drawbacks, most importantly its lack of physiologic data.

Clinical outcomes with ß-blockers for myocardial infarction: a meta-analysis of randomized trials.

BACKGROUND: Debate exists about the efficacy of ß-blockers in myocardial infarction and their required duration of usage in contemporary practice. METHODS: We conducted a MEDLINE/EMBASE/CENTRAL search for randomized trials evaluating ß-blockers in myocardial infarction enrolling at least 100 patients. The primary outcome was all-cause mortality. Analysis was performed stratifying trials into reperfusion-era (> 50% undergoing reperfusion or receiving aspirin/statin) or pre-reperfusion-era trials. RESULTS: Sixty trials with 102,003 patients satisfied the inclusion criteria. In the acute myocardial infarction trials, a significant interaction (Pinteraction = .02) was noted such that ß-blockers reduced mortality in the pre-reperfusion (incident rate ratio [IRR] 0.86; 95% confidence interval [CI], 0.79-0.94) but not in the reperfusion era (IRR 0.98; 95% CI, 0.92-1.05). In the pre-reperfusion era, ß-blockers reduced cardiovascular mortality (IRR 0.87; 95% CI, 0.78-0.98), myocardial infarction (IRR 0.78; 95% CI, 0.62-0.97), and angina (IRR 0.88; 95% CI, 0.82-0.95), with no difference for other outcomes. In the reperfusion era, ß-blockers reduced myocardial infarction (IRR 0.72; 95% CI, 0.62-0.83) (number needed to treat to benefit [NNTB] = 209) and angina (IRR 0.80; 95% CI, 0.65-0.98) (NNTB = 26) at the expense of increase in heart failure (IRR 1.10; 95% CI, 1.05-1.16) (number needed to treat to harm [NNTH] = 79), cardiogenic shock (IRR 1.29; 95% CI, 1.18-1.41) (NNTH = 90), and drug discontinuation (IRR 1.64; 95% CI, 1.55-1.73), with no benefit for other outcomes. Benefits for recurrent myocardial infarction and angina in the reperfusion era appeared to be short term (30 days). CONCLUSIONS: In contemporary practice of treatment of myocardial infarction, ß-blockers have no mortality benefit but reduce recurrent myocardial infarction and angina (short-term) at the expense of increase in heart failure, cardiogenic shock, and drug discontinuation. The guideline authors should reconsider the strength of recommendations for ß-blockers post myocardial infarction.

Association of exercise tolerance with effective arterial elastance obtained noninvasively in patients with exertional dyspnea.

BACKGROUND: Ventricular-arterial stiffening is a part of the aging process that is amplified by various comorbidities. It affects normal cardiovascular reserve and limits exercise capacity. The aim of this study was to explore the association of physiologic determinants of ventricular-arterial interaction with exercise capacity in patients referred for exercise echocardiography with exertional dyspnea. METHODS: A total of 93 patients with exertional dyspnea without chest pain were evaluated using the Bruce protocol. Patients with left ventricular ejection fractions < 50% and those with exercise-induced myocardial ischemia were excluded. Poor exercise tolerance was defined as inability to achieve 8 metabolic equivalents. RESULTS: Thirty-seven patients (40%) had poor exercise tolerance. These patients were older (mean age, 60 vs 54 years, P = .01), more likely to carry the diagnosis of hypertension (84% vs 41%, P < .01), and more likely to be treated with antihypertensive medications. In multivariate logistic regression analysis, left atrial volume index (P = .04) and arterial elastance (P < .01) were significant predictor of poor exercise capacity, while left ventricular ejection fraction, tissue Doppler indices, and global longitudinal strain were not significant. CONCLUSIONS: Effective arterial elastance determined noninvasively before stress echocardiography appears to be an independent predictor of exercise tolerance in patients with exertional dyspnea.

Feasibility and prognostic value of stress echocardiography in obese, morbidly obese, and super obese patients referred for bariatric surgery.

BACKGROUND: Stress echocardiography (SE) is clinically used in the risk stratification and prognosis of patients with coronary artery disease. Due to multiple comorbidities, obese patients have increased risk of adverse cardiovascular events perioperatively in noncardiac surgery. The aim of this study was to investigate the feasibility of SE in morbidly obese patients undergoing bariatric surgery. METHODS: Consecutive patients referred for SE for preoperative evaluation prior to bariatric surgery from January 2002 to July 2011 formed the study cohort. Contrast was used to define the endocardial border in patients with poor acoustic windows. All-cause mortality data were obtained from Social Security Death Index. RESULTS: Six hundred fifty-two patients (47 ± 10 years, 84% females) with the mean follow-up of 3.0 ± 2.7 years and mean body mass index (BMI) of 47 ± 9 kg/m² were included in this analysis. Dobutamine SE was performed in 65% of patients compared to exercise SE in 35%. Patients with higher BMI were more likely to undergo dobutamine SE (P < 0.0001). Similarly, incidence of poor acoustic windows and contrast use was higher in those with increased BMI (P < 0.001). Contrast use was higher in patients undergoing dobutamine SE (39%) versus exercise (25%), (P = 0.002). 19 patients (3%) had an abnormal SE and 8 patients (1.2%) died during the follow-up period. CONCLUSION: Stress echocardiography is feasible in the morbidly obese patients. Patients with higher BMI were more likely to undergo dobutamine SE and have higher incidence of poor acoustic windows and contrast use.

Antihypertensive efficacy of angiotensin receptor blockers as monotherapy as evaluated by ambulatory blood pressure monitoring: a meta-analysis.

AIMS: Angiotensin receptor blockers (ARBs) are available in different dosages and it is common clinical practice to uptitrate if blood pressure goal is not achieved with the initial dose. Data on the incremental antihypertensive efficacy with uptitration are scarce. It is also unclear if antihypertensive efficacy of losartan is comparable with other ARBs. METHODS AND RESULTS: We systematically reviewed PubMed/EMBASE/Cochrane databases for all randomized clinical trials until December 2012 reporting 24 h ambulatory blood pressure (ABP) for most commonly available ARBs in patients with hypertension. Reduction in ABP with ARBs was evaluated at 25% of the maximum (max) dose, 50% of the max dose, and at the max dose. Comparison was made between 24 h BP-lowering effect of losartan 50 and 100 mg and other ARBs at 50% max dose and the max dose, respectively. Sixty-two studies enrolling 15 289 patients (mean age 56 years; 60% men) with a mean duration of 10 weeks were included in the analysis. Overall, the dose-response curve with ARBs was shallow with decrease of 10.3/6.7 (systolic/diastolic), 11.7/7.6, and 13.0/8.3 mmHg with 25% max dose, 50% max dose, and with the max dose of ARBs, respectively. Losartan in the dose of 50 mg lowered ABP less well than other ARBs at 50% max dose by 2.5 mmHg systolic (P < 0.0001) and 1.8 mmHg diastolic (P = 0.0003). Losartan 100 mg lowered ABP less well than other ARBs at max dose by 3.9 mm Hg systolic (P = 0.0002) and 2.2 mmHg diastolic (P = 0.002). CONCLUSION: In this comprehensive analysis of the antihypertensive efficacy of ARBs by 24 h ABP, we observed a shallow dose-response curve, and uptitration marginally enhanced the antihypertensive efficacy. Blood pressure reduction with losartan at starting dose and at max dose was consistently inferior to the other ARBs.

Meta-analysis of prognostic implications of dyspnea versus chest pain in patients referred for stress testing.

Previous studies have suggested that patients with dyspnea referred for stress testing have high mortality. However, it is not clear whether this is explained by high rates of ischemia. The aim of the present study was to evaluate the incidence of ischemia in patients with dyspnea compared with patients with chest pain referred for stress testing and assess the outcomes of such patients. We systematically searched the electronic databases, MEDLINE, PubMed, EMBASE, and the Cochrane Library, until December 2012 to identify studies of patients with known or suspected coronary artery disease undergoing stress testing. We extracted data on group-specific incidence of stress-induced ischemia and all-cause mortality. In our analyses, we identified and included 6 studies that evaluated a total of 5,753 patients with dyspnea and 24,491 patients with chest pain as the clinical indication for stress testing. There was no statistically significant difference in the incidence of ischemia on stress imaging in patients with dyspnea compared with patients with chest pain (37.4% vs 30.2%, odds ratio 1.43, 95% confidence interval 0.99 to 2.06, p = 0.06). However, during the follow-up period, patients with dyspnea had higher all-cause mortality rates compared with patients with chest pain (annual mortality 4.9% vs 2.3%), with odds ratio of 2.57 (95% confidence interval 1.75 to 3.76, p <0.001). In conclusion, in patients undergoing stress testing, those evaluated for dyspnea had a significant increase in all-cause mortality but did not have higher rates of ischemia compared with patients presenting with chest pain. Clinicians evaluating patients with self-reported dyspnea should be aware that these patients represent a high-risk group with increased risk of mortality.

CMR imaging for the evaluation of myocardial stunning after acute myocardial infarction: a meta-analysis of prospective trials.

BACKGROUND: Myocardial stunning is an important sequela of acute coronary syndromes and its determination might affect decisions on defibrillator implantation and assist devices after myocardial infarction (AMI). The aim of the study was to evaluate and compare the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of cardiac magnetic resonance imaging (CMR) assessing myocardial stunning after acute myocardial infarction using low-dose dobutamine (LDD), end-diastolic wall thickness, and contrast delayed enhancement (DE). METHODS AND RESULTS: A systematic review of Medline, Embase, and Cochrane for all prospective trials assessing myocardial stunning by CMR following AMI was performed using a standard approach for meta-analysis for diagnostic test and a bivariate analysis. Search results revealed 9384 studies, out of which 17 met criteria. A total of 634 patients (mean age 59 years, 85% male, mean left ventricular ejection fraction: 52%) were included. DE-CMR had a weighted sensitivity of 87% and specificity of 68% to detect myocardial stunning using 50% transmurality as a cut-off, with a PPV and NPV of 83 and 72%, respectively. With an overall diagnostic accuracy of 82%, LDD-CMR had a sensitivity of 67% and a specificity of 81%, with a PPV and NPV of 82 and 63%, respectively. LDD showed an overall accuracy of 74%. CONCLUSION: DE-CMR has a higher sensitivity, whereas LDD-CMR has a higher specificity for the detection of viable stunned myocardium following myocardial infarction. Whether the combination of DE and LDD may improve the prediction of myocardial recovery remains to be determined.

Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials.

OBJECTIVE: To compare the long term efficacy and adverse events of dual blockade of the renin-angiotensin system with monotherapy. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, and the Cochrane central register of controlled trials, January 1990 to August 2012. STUDY SELECTION: Randomised controlled trials comparing dual blockers of the renin-angiotensin system with monotherapy, reporting data on either long term efficacy (≥ 1 year) or safety events (≥ 4 weeks), and with a sample size of at least 50. Analysis was stratified by trials with patients with heart failure versus patients without heart failure. RESULTS: 33 randomised controlled trials with 68,405 patients (mean age 61 years, 71% men) and mean duration of 52 weeks were included. Dual blockade of the renin-angiotensin system was not associated with any significant benefit for all cause mortality (relative risk 0.97, 95% confidence interval 0.89 to 1.06) and cardiovascular mortality (0.96, 0.88 to 1.05) compared with monotherapy. Compared with monotherapy, dual therapy was associated with an 18% reduction in admissions to hospital for heart failure (0.82, 0.74 to 0.92). However, compared with monotherapy, dual therapy was associated with a 55% increase in the risk of hyperkalaemia (P<0.001), a 66% increase in the risk of hypotension (P<0.001), a 41% increase in the risk of renal failure (P=0.01), and a 27% increase in the risk of withdrawal owing to adverse events (P<0.001). Efficacy and safety results were consistent in cohorts with and without heart failure when dual therapy was compared with monotherapy except for all cause mortality, which was higher in the cohort without heart failure (P=0.04 v P=0.15), and renal failure was significantly higher in the cohort with heart failure (P<0.001 v P=0.79). CONCLUSION: Although dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events such as hyperkalaemia, hypotension, and renal failure compared with monotherapy. The risk to benefit ratio argues against the use of dual therapy.

Cardiac outcomes with submaximal normal stress echocardiography: a meta-analysis.

OBJECTIVES: The aim of the study was to evaluate the risk of cardiac events in patients with normal stress echocardiography (SE) who attained maximal age-predicted heart rate (APHR) compared with those who did not in the setting of both normal and abnormal SE. BACKGROUND: SE is an important tool in the risk stratification and prognosis of patients with known or suspected coronary artery disease (CAD). The prognostic value of a normal but submaximal SE (<85% of maximal APHR) is conflicting. METHODS: PubMed, EMBASE, and CENTRAL were searched from 1980 to September 2011 for SE studies reporting cardiac outcomes in patients with known or suspected CAD stratified by achieved APHR. Both hard events (cardiac death and myocardial infarction) and total cardiac events (revascularization procedures in addition to hard events) were analyzed separately. Data on all-cause mortality were obtained when available. RESULTS: Fourteen studies with 11,542 patients followed up for a mean duration of 32 months fulfilled the inclusion criteria. In 8 studies with 4,577 patients, the risk of hard events with normal SE (both exercise and dobutamine) was 70% higher in patients who achieved submaximal compared with those with maximal APHR (annualized event rate 2.08% vs. 0.77%; p=0.0008; 95% confidence interval [CI]: 1.25 to 2.31). In 7 studies with 5,798 patients, the risk of total cardiac events with normal SE (both exercise and dobutamine) was 127% higher in patients who achieved submaximal compared with those with maximal APHR (annualized event rate 1.87% vs. 1.02%; p<0.0001; 95% CI: 1.54 to 3.34). The risk of total cardiac events was 278% higher in patients with abnormal SE with submaximal APHR compared with those with normal SE with submaximal APHR (p<0.0001; 95% CI: 2.81 to 5.08). There was a trend toward increased all-cause mortality in patients with normal SE with submaximal compared with maximal APHR (relative risk: 1.36; p=0.15; 95% CI: 0.89 to 2.09). CONCLUSIONS: Patients with submaximal APHR in the setting of normal SE have a higher risk of cardiovascular events than those who attained maximal stress test. Thus, the results of submaximal APHR in the setting of normal SE should be taken into consideration for more accurate risk stratification and prognosis.

Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors.

Angioedema is a rare, potentially life-threatening adverse event of renin-angiotensin system inhibitors. The objective of the present study was to determine the risk of angioedema from randomized clinical trials. A PubMed/CENTRAL/EMBASE search was made for randomized clinical trials from 1980 to October 2011 in patients on angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or direct renin inhibitor (DRI). Trials with a total number of patients ≥100 and a duration of ≥8 weeks were included for analysis. Incidence of angioedema was pooled by weighing the incident rate of each trial by the inverse of the variance. Twenty-six trials with 74,857 patients in the ACE inhibitor arm with 232,523 person-years of follow-up, 19 trials with 35,479 patients on ARB with 122,293 person-years of follow-up, and 2 trials with 5,141 patients on DRI with 1,735 person-years of follow-up met the inclusion criteria and were included in the analysis. In head-to-head comparison in 7 trials, risk of angioedema with ACE inhibitors was 2.2 times higher than with ARBs (95% confidence interval [CI] 1.5 to 3.3). With ACE inhibitors and ARBs, incidence of angioedema was higher in heart failure trials compared to hypertension or coronary artery disease trials without heart failure (p <0.0001). Weighted incidence of angioedema with ACE inhibitors was 0.30% (95% CI 0.28 to 0.32) compared to 0.11% (95% CI 0.09 to 0.13) with ARBs, 0.13% (95% CI 0.08 to 0.19) with DRIs, and 0.07% with placebo (95% CI 0.05 to 0.09). In conclusion, incidence of angioedema with ARBs and DRI was <1/2 than that with ACE inhibitors and not significantly different from placebo. Incidence of angioedema was higher in patients with heart failure compared to those without heart failure with ACE inhibitors and ARBs.

Risk stratification and prognosis of human immunodeficiency virus-infected patients with known or suspected coronary artery disease referred for stress echocardiography.

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 χ(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.

Peripheral edema associated with calcium channel blockers: incidence and withdrawal rate--a meta-analysis of randomized trials.

OBJECTIVE: Peripheral edema is considered to be a common and annoying adverse effect of calcium channel blockers (CCBs). It has been thought to occur secondary to arteriolar dilatation causing intracapillary hypertension and fluid extravasation. We aimed to evaluate the incidence and withdrawal rate of peripheral edema with CCBs. METHODS: A systematic search was made in PubMed, EMBASE and CENTRAL from 1980 to January 2011 for randomized clinical trials reporting peripheral edema with CCBs in patients with hypertension. Trials enrolling at least 100 patients in the CCB arm and lasting at least 4 weeks were included in the analysis. Both the incidence and withdrawal rate due to edema were pooled by weighing each trial by the inverse of the variance. Head-to-head comparison was done to evaluate the risk of edema between newer lipophilic dihydropyridine (DHP) CCBs and older DHPs. RESULTS: One hundred and six studies with 99 469 participants, mean age 56 ± 6 years, satisfied our inclusion criteria and were included in this analysis. The weighted incidence of peripheral edema was significantly higher in the CCBs group when compared with controls/placebo (10.7 vs. 3.2%, P < 0.0001). Similarly, the withdrawal rate due to edema was higher in patients on CCBs compared with control/placebo (2.1 vs. 0.5%, P < 0.0001). Both the incidence of edema and patient withdrawal rate due to edema increased with the duration of therapy with CCBs reaching 24 and 5%, respectively, after 6 months. The risk of peripheral edema with lipophilic DHPs was 57% lower than with traditional DHPs (relative risk 0.43; 95% confidence interval 0.34-0.53; P < 0.0001). Incidence of peripheral edema in patients on DHPs was 12.3% compared with 3.1% with non-DHPs (P < 0.0001). Edema with high-dose CCBs (defined as more than half the usual maximal dose) was 2.8 times higher than that with low-dose CCBs (16.1 vs. 5.7%, P < 0.0001). CONCLUSION: The incidence of peripheral edema progressively increased with duration of CCB therapy up to 6 months. Over the long term, more than 5% of patients discontinued CCBs because of this adverse effect. Edema rates were lower with both non-DHPs and lipophilic DHPs.

Effect of renin-angiotensin system blockade on calcium channel blocker-associated peripheral edema.

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.