Pavel Hoffmann

Efficacy and Safety of Immediate Angioplasty Versus Ischemia-Guided Management After Thrombolysis in Acute Myocardial Infarction in Areas With Very Long Transfer Distances Results of the NORDISTEMI (NORwegian study on DIstrict treatment of ST-Elevation Myocardial Infarction)

OBJECTIVES The goal of this study was to compare a strategy of immediate transfer for percutaneous coronary intervention (PCI) with an ischemia-guided approach after thrombolysis in patients with very long transfer distances to PCI. BACKGROUND Thrombolysis remains the treatment of choice in ST-segment elevation myocardial infarction (STEMI) when primary PCI cannot be performed within 90 to 120 min. The optimal treatment after thrombolysis is still unclear. METHODS A total of 266 patients with acute STEMI living in rural areas with more than 90-min transfer delays to PCI were treated with tenecteplase, aspirin, enoxaparin, and clopidogrel and randomized to immediate transfer for PCI or to standard management in the local hospitals with early transfer, only if indicated for rescue or clinical deterioration. The primary outcome was a composite of death, reinfarction, stroke, or new ischemia at 12 months, and analysis was by intention to treat. RESULTS The primary end point was reached in 28 patients (21%) in the early invasive group compared with 36 (27%) in the conservative group (hazard ratio: 0.72, 95% confidence interval: 0.44 to 1.18, p = 0.19). The composite of death, reinfarction, or stroke at 12 months was significantly reduced in the early invasive compared with the conservative group (6% vs. 16%, hazard ratio: 0.36, 95% confidence interval: 0.16 to 0.81, p = 0.01). No significant differences in bleeding or infarct size were observed. CONCLUSIONS Immediate transfer for PCI did not improve the primary outcome significantly, but reduced the rate of death, reinfarction, or stroke at 12 months in patients with STEMI, treated with thrombolysis and clopidogrel in areas with long transfer distances. (Norwegian Study on District Treatment of ST-Elevation Myocardial Infarction; NCT00161005).

Adjusted Drug Treatment Is Superior to Renal Sympathetic Denervation in Patients With True Treatment-Resistant Hypertension

&NA; We aimed to investigate for the first time the blood pressure (BP)–lowering effect of renal sympathetic denervation (RDN) versus clinically adjusted drug treatment in true treatment-resistant hypertension (TRH) after excluding patients with confounding poor drug adherence. Patients with apparent TRH (n=65) were referred for RDN, and those with secondary and spurious hypertension (n=26) were excluded. TRH was defined as office systolic BP (SBP) >140 mm Hg, despite maximally tolerated doses of ≥3 antihypertensive drugs including a diuretic. In addition, ambulatory daytime SBP >135 mm Hg after witnessed intake of antihypertensive drugs was required, after which 20 patients had normalized BP and were excluded. Patients with true TRH were randomized and underwent RDN (n=9) performed with Symplicity Catheter System versus clinically adjusted drug treatment (n=10). The study was stopped early for ethical reasons because RDN had uncertain BP-lowering effect. Office SBP and diastolic BP in the drug-adjusted group changed from 160±14/88±13 mm Hg (±SD) at baseline to 132±10/77±8 mm Hg at 6 months (P<0.0005 and P=0.02, SBP and diastolic BP, respectively) and in the RDN group from 156±13/91±15 to 148±7/89±8 mm Hg (P=0.42 and P=0.48, SBP and diastolic BP, respectively). SBP and diastolic BP were significantly lower in the drug-adjusted group at 6 months (P=0.002 and P=0.004, respectively), and absolute changes in SBP were larger in the drug-adjusted group (P=0.008). Ambulatory BPs changed in parallel to office BPs. Our data suggest that adjusted drug treatment has superior BP lowering effects compared with RDN in patients with true TRH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01673516

Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol

Abstract Aims Contemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the β-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation. Methods and results In a 2 × 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the β-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed. Conclusion In patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function.

Renal Sympathetic Denervation in Patients With Treatment-Resistant Hypertension After Witnessed Intake of Medication Before Qualifying Ambulatory Blood Pressure

&NA;It is unknown whether the decline in blood pressure (BP) after renal denervation (RDN) is caused by denervation itself or concomitantly improved drug adherence. We aimed to investigate the BP lowering effect of RDN in true treatment-resistant hypertension by excluding patients with poor drug adherence. Patients with resistant hypertension (n=18) were referred for a thorough clinical and laboratory work-up. Treatment-resistant hypertension was defined as office systolic BP>140 mm Hg, despite maximally tolerated doses of ≥3 antihypertensive drugs, including a diuretic. In addition, ambulatory daytime systolic BP>135 mm Hg was required after witnessed intake of antihypertensive drugs to qualify. RDN (n=6) was performed with Symplicity Catheter System. The mean office and ambulatory BPs remained unchanged at 1, 3, and 6 months in the 6 patients, whereas there was no known change in antihypertensive medication. Two patients, however, had a fall in both office and ambulatory BPs. Our findings question whether BP falls in response to RDN in patients with true treatment-resistant hypertension. Additional research must aim to verify potential BP lowering effect and identify a priori responders to RDN before this invasive method can routinely be applied to patients with drug-resistant hypertension. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01673516.

Effect of Ischemic Postconditioning on Infarct Size in Patients With ST-Elevation Myocardial Infarction Treated by Primary PCI Results of the POSTEMI (POstconditioning in ST-Elevation Myocardial Infarction) Randomized Trial

Background Reduction of infarct size by ischemic postconditioning (IPost) has been reported in smaller proof‐of‐concept clinical studies, but has not been confirmed in other smaller studies. The principle needs to be evaluated in larger groups of ST‐elevation myocardial infarction (STEMI) patients before being implemented in clinical practice. This study assessed the effect of ischemic postcoditioning (IPost) on infarct size in patients with STEMI treated by primary percutaneous coronary intervention (PCI). Methods and Results Patients with first‐time STEMI, <6 hours from symptom onset, referred to primary PCI were randomized to IPost or control groups. IPost was administered by 4 cycles of 1‐minute reocclusion and 1‐minute reperfusion, starting 1 minute after opening, followed by stenting. In the control group, stenting was performed immediately after reperfusion. The primary endpoint was infarct size measured by cardiac magnetic resonance after 4 months. A total of 272 patients were randomized. Infarct size (percent of left ventricular mass) after 4 months (median values and interquartile range) was 14.4% (7.7, 24.6) and 13.5% (8.1, 19.3) in the control group and IPost group, respectively (P=0.18). No significant impact of IPost was found when controlling for baseline risk factors of infarct size in a multivariate linear regression model (P=0.16). The effects of IPost on secondary endpoints, including markers of necrosis, myocardial salvage, and ejection fraction, as well as adverse cardiac events during follow‐up, were consistently neutral. Conclusions In contrast to several smaller trials reported previously, we found no significant effects of IPost on infarct size or secondary study outcomes. Clinical Trial Registration URL: http://www.clinicaltrials.gov Unique identifier: NCT.No.PO1506.

Rationale and Design of the Prevention of Cardiac Dysfunction during an Adjuvant Breast Cancer Therapy (PRADA) Trial

Objective: The PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) study is a randomized, placebo-controlled, double-blind trial to determine whether angiotensin receptor blockers (ARB), or beta-blockers or their combination may prevent the development of left ventricular (LV) dysfunction in patients on standard adjuvant treatment for early breast cancer. Methods: Following surgical resection, 120 breast cancer patients scheduled for adjuvant epirubicin-containing chemotherapy and, if indicated, trastuzumab, will be included. They will be randomized to an ARB (candesartan), a beta-blocker (metoprolol) and matching placebos in a 2 × 2 factorial design. The primary objective of the PRADA study is to assess whether prophylactic ARB and/or beta-blockers may prevent a reduction in LV ejection fraction (EF) after adjuvant treatment of early breast cancer, as evaluated by serial cardiovascular magnetic resonance (CMR) performed at randomization, after the first chemotherapy cycle and on its completion, and for subgroups, on completion of radiotherapy or trastuzumab. Secondary outcome measures include echocardiographic indices of LV diastolic dysfunction, structural myocardial alterations assessed by CMR and changes in cardiac biomarkers. Conclusion: PRADA may provide new information on the prophylactic effect of ARB and beta-blockers in patients with early breast cancer regarding the risk of developing cardiac dysfunction from adjuvant cancer treatment.

Assessment of left ventricular function with magnetic resonance imaging vs. echocardiography, contrast echocardiography, and single-photon emission computed tomography in patients with recent ST-elevation myocardial infarction

AIMS Magnetic resonance imaging (MRI) is often considered to be the gold standard in measuring left ventricular function and volumes. The aim of this study was to assess the agreements between standard echocardiography (standard echo), contrast echocardiography (contrast echo), single-photon emission computed tomography (SPECT), and MRI in the determination of left ventricular ejection fraction (EF) and end-diastolic volumes (EDV) in patients treated for acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS Standard echo, contrast echo, SPECT and MRI were performed on the same day, 3 months after STEMI in 150 patients participating in the NORwegian Study on District Treatment of ST-Elevation Myocardial Infarction (NORDISTEMI). Bland-Altman analysis of EF measured by all four imaging modalities showed generally low mean differences but wide limits of agreement. The mean EDV difference, however, was consistently higher when MRI was compared with standard echo (54.9 mL), contrast echo (41.7 mL) and SPECT (54.6 mL), and the limits of agreement were wider. The mean EDV differences between contrast echo vs. standard echo, SPECT vs. standard echo and contrast echo vs. SPECT were small. CONCLUSION Our data suggest that all four imaging modalities measured EF closely similar after STEMI as demonstrated by a very small bias. The limits of agreement were however wide. EDV measured by MRI was consistently higher when compared with the other methods which may be caused by different tracing-methods and imaging principles. As echocardiography is preferable from a cost-benefit point of view, further analysis would be needed to clarify the nature of such differences.

Multi-vendor, multicentre comparison of contrast-enhanced SSFP and T2-STIR CMR for determining myocardium at risk in ST-elevation myocardial infarction

Aims Myocardial salvage, determined by cardiac magnetic resonance imaging (CMR), is used as end point in cardioprotection trials. To calculate myocardial salvage, infarct size is related to myocardium at risk (MaR), which can be assessed by T2-short tau inversion recovery (T2-STIR) and contrast-enhanced steady-state free precession magnetic resonance imaging (CE-SSFP). We aimed to determine how T2-STIR and CE-SSFP perform in determining MaR when applied in multicentre, multi-vendor settings. Methods and results A total of 215 patients from 17 centres were included after percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction. CMR was performed within 1–8 days. These patients participated in the MITOCARE or CHILL-MI cardioprotection trials. Additionally, 8 patients from a previous study, imaged 1 day post-CMR, were included. Late gadolinium enhancement, T2-STIR, and CE-SSFP images were acquired on 1.5T MR scanners (Philips, Siemens, or GE). In 65% of the patients, T2-STIR was of diagnostic quality compared with 97% for CE-SSFP. In diagnostic quality images, there was no difference in MaR by T2-STIR and CE-SSFP (bias: 0.02 ± 6%, P = 0.96, r2 = 0.71, P < 0.001), or between treatment and control arms. No change in size or quality of MaR nor ability to identify culprit artery was seen over the first week after the acute event (P = 0.44). Conclusion In diagnostic quality images, T2-STIR and CE-SSFP provide similar estimates of MaR, were constant over the first week, and were not affected by treatment. CE-SSFP had a higher degree of diagnostic quality images compared with T2 imaging for sequences from two out of three vendors. Therefore, CE-SSFP is currently more suitable for implementation in multicentre, multi-vendor clinical trials.

Rationale and Design of the POSTEMI (Postconditioning in ST-Elevation Myocardial Infarction) Study

Rapid reperfusion of the infarct-related coronary artery is essential in the treatment of acute ST-elevation myocardial infarction (STEMI). Paradoxically, restoration of the blood flow to the ischemic area may result in further injury to the myocardium. This phenomenon is described as ‘ischemia/reperfusion injury’ and the pathophysiological mechanisms are not fully elucidated. A cardioprotective effect of ischemic postconditioning (short repetitive cycles of reperfusion and re-occlusion) has been demonstrated in experimental studies and in pilot studies on patients with acute STEMI treated with primary percutaneous coronary intervention. We present the study design of the Postconditioning in ST-Elevation Myocardial Infarction (POSTEMI) study, which is a prospective, randomized, open-label clinical trial with blinded endpoint evaluation designed to evaluate the effect of postconditioning on final infarct size. Patients with acute STEMI with symptoms of less than 6 h and proximal or mid-coronary artery occlusion will be included. The primary endpoint is infarct size, assessed by cardiac MRI after 4 months. The secondary endpoints are to evaluate the effect of postconditioning on TIMI myocardial perfusion grade, resolution of ST-segment elevation, release of markers of ischemia, left ventricular function and final infarct size related to the area at risk. A total of 260 patients will be included in the study.

Inflammatory responses after percutaneous coronary intervention in patients with acute myocardial infarction or stable angina pectoris

Objective. To investigate the profile of circulating inflammatory markers after percutaneous coronary intervention (PCI) in patients with AMI or stable angina pectoris (AP). Material and methods. Twenty patients with AMI and 10 with stable AP were treated with PCI of a central coronary artery. Blood samples were drawn immediately before PCI, in the AP group and after 3 and 12 h, days 1, 3, 5, 7 and 14 in both groups. Results. Interleukin 6 increased in both groups to time‐point 12 h and day 1 (peak), being significantly higher in the AMI group compared to the AP group at 3 and 12 h, and also at days 1 and 3. A similar profile was demonstrated for CRP with significantly higher levels in the AMI group at days 1, 3 and 5 compared to the AP group. A slightly different pattern was shown for Interleukin 10 (IL‐10) with significantly higher levels in the AMI group at 3 and 12 h, days 1 and 14 compared to the AP group. Conclusion. AMI patients treated with PCI experienced a marked short‐term increase in pro‐inflammatory mediators as well as IL‐10 compared to patients with stable angina pectoris treated with PCI.