Hans-Peter Brunner-La Rocca

Drug-Eluting versus Bare-Metal Stents in Large Coronary Arteries

BACKGROUND Recent data have suggested that patients with coronary disease in large arteries are at increased risk for late cardiac events after percutaneous intervention with first-generation drug-eluting stents, as compared with bare-metal stents. We sought to confirm this observation and to assess whether this increase in risk was also seen with second-generation drug-eluting stents. METHODS We randomly assigned 2314 patients needing stents that were 3.0 mm or more in diameter to receive sirolimus-eluting, everolimus-eluting, or bare-metal stents. The primary end point was the composite of death from cardiac causes or nonfatal myocardial infarction at 2 years. Late events (occurring during months 7 to 24) and target-vessel revascularization were the main secondary end points. RESULTS The rates of the primary end point were 2.6% among patients receiving sirolimus-eluting stents, 3.2% among those receiving everolimus-eluting stents, and 4.8% among those receiving bare-metal stents, with no significant differences between patients receiving either drug-eluting stent and those receiving bare-metal stents. There were also no significant between-group differences in the rate of late events or in the rate of death, myocardial infarction, or stent thrombosis. Rates of target-vessel revascularization for reasons unrelated to myocardial infarction were 3.7% among patients receiving sirolimus-eluting stents, 3.1% among those receiving everolimus-eluting stents, and 8.9% among those receiving bare-metal stents. The rate of target-vessel revascularization was significantly reduced among patients receiving either drug-eluting stent, as compared with a bare-metal stent, with no significant difference between the two types of drug-eluting stents. CONCLUSIONS In patients requiring stenting of large coronary arteries, no significant differences were found among sirolimus-eluting, everolimus-eluting, and bare-metal stents with respect to the rate of death or myocardial infarction. With the two drug-eluting stents, similar reductions in rates of target-vessel revascularization were seen. (Funded by the Basel Cardiovascular Research Foundation and the Swiss National Foundation for Research; Current Controlled Trials number, ISRCTN72444640.).

Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.

Context Very few trials have evaluated ways to prevent high-altitude pulmonary edema (HAPE). Contribution In this double-blind trial, 29 adults with a history of HAPE were randomly assigned to receive prophylactic tadalafil, dexamethasone, or placebo during a 24-hour ascent and 2-day stay at 4559 m. Compared with placebo recipients, adults taking dexamethasone less often experienced acute mountain sickness and those taking either dexamethasone or tadalafil less often had HAPE. Cautions The trial involved a small number of selected adults who rapidly ascended to a high altitude. Implications Either tadalafil or dexamethasone might help prevent HAPE in mountaineers with a history of pulmonary edema. The Editors Rapid ascent to altitudes greater than 2500 m may cause acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE). In nonacclimatized mountaineers, the prevalences of AMS and HAPE at 4559 m are approximately 50% and 4%, respectively (1). Individual susceptibility, rate of ascent, and preexposure to high altitude are major, independent determinants of the prevalence of AMS (2). Acute mountain sickness is not a prerequisite for HAPE. Acetazolamide (3, 4) or dexamethasone (5, 6) prophylaxis can prevent AMS, whereas nifedipine prophylaxis can prevent HAPE (7). Whether acetazolamide or dexamethasone also prevents HAPE has not been studied. Exaggerated hypoxic pulmonary vasoconstriction leading to elevated pulmonary capillary pressure (8) is the major pathophysiologic mechanism of HAPE. This elevated pulmonary capillary pressure may be caused by inhomogeneous hypoxic pulmonary vasoconstriction (9), which leads to areas that are subjected to high pressure and flow, consequent mechanical overdistention of pulmonary capillaries, and injury of the bloodgas barrier (10). This phenomenon causes extravasation of fluid, plasma proteins, and blood cells into the interstitial and alveolar spaces (11). Decreased bioavailability of nitric oxide might explain the elevated pulmonary artery pressure (12, 13). Therefore, phosphodiesterase-5 inhibitors are an attractive option to restore impaired effects of nitric oxide in persons susceptible to HAPE (1416). Constitutively impaired sodium and water transport in the lung has been thought to be an additional factor in the pathogenesis of HAPE (17, 18). Hypoxia also decreases water reabsorption from the alveolar space. Direct experimental evidence has been obtained from hypoxia-exposed rats (19), and indirect evidence derives from decreased sodium transport activity in cultured alveolar epithelial cells (20). Prophylactic inhalation of the 2-adrenergic agonist salmeterol to stimulate alveolar sodium transport (17) decreased the incidence of HAPE in susceptible persons. However, other mechanisms of action may also contribute to the preventive effects of salmeterol, because -adrenergics tighten the endothelial barrier and decrease pulmonary artery pressure (21). Dexamethasone may be an alternative therapy to prevent HAPE because it stimulates alveolar sodium and water reabsorption (22); may enhance nitric oxide availability in pulmonary vessels (23, 24); and is effective against AMS (5, 6), which may develop despite use of nifedipine as prophylaxis against HAPE (25). However, HAPE has occurred in persons who received dexamethasone for AMS (26, 27). We sought to test whether prophylaxis with dexamethasone or tadalafil reduces the risk for HAPE in adults with a history of HAPE on rapid ascent to 4559 m. Methods Sample and Setting Mountaineers with a history of HAPE were recruited through announcements in the journals of the Swiss Alpine Club and the German Alpine Club. Four women and 25 men with at least 1 documented episode of HAPE participated after providing written informed consent. Table 1 shows the age and average number of HAPE episodes for each participant. No participant spent more than 4 nights above 2500 m within 30 days before ascent to the Capanna Regina Margherita, Italy (altitude, 4559 m). Table 1. Participant Characteristics Two to 4 weeks before the study at the Capanna Regina Margherita, baseline evaluations were performed in Zrich, Switzerland (altitude, 490 m). For ascent, participants traveled to Alagna, Italy (altitude, 1100 m), ascended to 3200 m by cable car, and continued by foot to the Capanna Gnifetti (altitude, 3600 m), where they spent 1 night. The journey from the cable car arrival station (3200 m) to the Capanna Gnifetti took about 1.5 hours. The next morning, the participants continued to the Capanna Regina Margherita (about 4 hours), where they spent 2 nights. Figure 1 shows the study design. The institutional ethics boards of the University Hospital Zrich and University Hospital Heidelberg approved the study and its protocol, which was consistent with the principles of the Declaration of Helsinki. Figure 1. Flow diagram of the study. Twenty-nine participants were recruited and underwent prealtitude tests, after which they were randomly assigned to treatment groups. *Two participants in the tadalafil group were withdrawn from the study early because they required treatment for severe acute mountain sickness (AMS) with oxygen and dexamethasone before the first night at 4559 m, but high-altitude pulmonary edema (HAPE) was not diagnosed at the time of withdrawal. However, the duration of exposure to 4559 m may not have been long enough to develop HAPE. Randomization and Interventions Medication consisted of white gelatin capsules, identical in appearance, containing placebo; tadalafil, 10 mg (Cialis [Eli Lilly, Geneva, Switzerland]); or dexamethasone, 8 mg (Fortecortin [Merck, Dietikon, Switzerland]). Before the study, the pharmacist at the University Hospital Zrich packaged the medication into numbered bottles, which were assigned to individual participants according to a computer-generated list. Randomization was stratified by the number of previous episodes of HAPE (1 or 2) without blocking. Participants started taking the medication twice daily on the morning of the day before ascent to high altitude and continued intake until the end of the study. Primary End Point and Assessment of HAPE and AMS The primary end point was development of HAPE, which was assessed by clinical examination and chest radiography in each participant after the first and second nights at 4559 m or when HAPE or severe AMS occurred (Figure 1). Two physicians who were blinded to treatment assignment performed clinical examinations according to a predefined checklist in the mornings after the first and second night at 4559 m or when severe AMS or HAPE occurred. High-altitude pulmonary edema was clinically suspected at the appearance of dry cough, orthopnea, or pulmonary rales in at least 1 lung area. A posteroanterior thorax radiograph was then obtained by using a mobile unit (TRS [Siemens, Stockholm, Sweden]) at a fixed distance of 1.4 m at 95 kV and a charge of 3 to 6 mAs. Radiographs were scored retrospectively by a second radiologist who was blinded to other study results. After the lung was divided into 4 quadrants, the following scores were assigned: 1 for a questionable infiltrate, 2 for interstitial edema in less than 50% of the quadrant area, 3 for interstitial edema on 50% or more of the quadrant area, and 4 for alveolar edema. A radiograph showing interstitial or alveolar edema (score >1) in at least 1 quadrant (28) confirmed the diagnosis of HAPE. The severity of AMS was evaluated by clinical examination and was quantified by using the Lake Louise scoring protocol (29). Each participant answered the first 5 questions of the protocol that asked about the severity of headache, gastrointestinal symptoms, fatigue, lightheadedness or dizziness, and insomnia. A score of 0 to 3 points (0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms) was assigned for each item. In clinical examination, a score of 0 (normal) to 4 points was given for mental status (for which 4 points indicated coma) and ataxia (for which 4 points indicated inability to stand on the heel-to-toe walking test). A score of 1 was given for peripheral edema in 1 location, and a score of 2 was given for edema in more than 1 location. The sum of all points yielded the Lake Louise score (maximum score, 25 points). A Lake Louise score greater than 4 defined AMS (30). To assess possible side effects of the study medications, we separately evaluated the Lake Louise score question that asked for information on headache severity and the degree of insomnia, and we measured blood glucose levels in addition to vital signs. To test for adherence, participants were requested to document medication intake and investigators counted the remaining capsules at each visit. Blood and urine samples were collected to measure cortisol and tadalafil, respectively. Treatment of HAPE and AMS consisted of nifedipine for HAPE, dexamethasone for AMS, and supplemental oxygen for both disorders. Participants who required treatment were withdrawn from the study. Echocardiography and Measurement of Cardiac Output Doppler echocardiography was performed by using an integrated color Doppler system with a 4.0-MHz transducer (Aplio 80 [Toshiba-Medical Systems, Oetwil am See, Switzerland]) while participants were lying in a semi-supine, left-lateral position. Systolic pulmonary artery pressure was calculated from the pressure gradient across the tricuspid valve and measured with continuous-wave Doppler echocardiography by using the modified Bernoulli equation and an estimated right atrial pressure of 7 mm Hg (8). Color flow imaging was used for alignment. The recordings were stored on magneto-optical disk for evaluation by 2 investigators who were blinded to all other data. Averages of at least 3 cardiac cycles were used. Cardiac output was measured by using beat-to-beat stroke volume measurement with impedance cardiography (Task Force Monitor [CNSystems, Graz, Austria]). Nasal Potential Measurements Diffe

Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis

Aims Natriuretic peptide-guided (NP-guided) treatment of heart failure has been tested against standard clinically guided care in multiple studies, but findings have been limited by study size. We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment of heart failure on all-cause mortality. Methods and results Eligible randomized clinical trials were identified from searches of Medline and EMBASE databases and the Cochrane Clinical Trials Register. The primary pre-specified outcome, all-cause mortality was tested using a Cox proportional hazards regression model that included study of origin, age (<75 or ≥75 years), and left ventricular ejection fraction (LVEF, ≤45 or >45%) as covariates. Secondary endpoints included heart failure or cardiovascular hospitalization. Of 11 eligible studies, 9 provided individual patient data and 2 aggregate data. For the primary endpoint individual data from 2000 patients were included, 994 randomized to clinically guided care and 1006 to NP-guided care. All-cause mortality was significantly reduced by NP-guided treatment [hazard ratio = 0.62 (0.45–0.86); P = 0.004] with no heterogeneity between studies or interaction with LVEF. The survival benefit from NP-guided therapy was seen in younger (<75 years) patients [0.62 (0.45–0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75–1.27); P = 0.96]. Hospitalization due to heart failure [0.80 (0.67–0.94); P = 0.009] or cardiovascular disease [0.82 (0.67–0.99); P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction with age or LVEF. Conclusion Natriuretic peptide-guided treatment of heart failure reduces all-cause mortality in patients aged <75 years and overall reduces heart failure and cardiovascular hospitalization.

Raised Sympathetic Nerve Activity in Heart Failure and Central Sleep Apnea Is Due to Heart Failure Severity

Background—Congestive heart failure (CHF) patients with central sleep apnea (CHF-CSA) have elevated plasma norepinephrine (NE) compared with CHF patients without apnea (CHF-N). Patients with CHF-CSA also demonstrate higher mean pulmonary artery pressure (PAP), which is suggestive of worse cardiac function. Whether CSA contributes to chronic elevation of sympathetic nerve activity or is associated with more severe CHF remains unknown. We measured awake total body and cardiac NE spillover and related these to measurements of cardiac hemodynamics and apnea severity in CHF patients with CSA, with normal breathing, and with obstructive sleep apnea (CHF-OSA). Methods and Results—A total of 55 CHF patients underwent right heart catheterization and measurements of total body and cardiac NE spillover using NE radioisotope dilution methodology. After polysomnography, patients were grouped by apnea type: 19 were CHF-N, 15 were CHF-OSA, and 21 were CHF-CSA. Compared with the CHF-N and CHF-OSA groups, the CHF-CSA group had significantly higher total body NE spillover (4.62±0.56 versus 4.47±0.54 versus 6.95±0.89 nmol/min, respectively;P =0.03), cardiac NE spillover (0.25±0.05 versus 0.21±0.05 versus 0.42±0.06 nmol/min, respectively;P =0.02) and mean PAP (23.5±2.4 versus 21.2±0.8 versus 30.4±0.2 mm Hg, respectively;P <0.02). However, controlling for severity of CHF resulted in no significant differences in NE kinetics among the 3 groups. In a stepwise regression, only mean PAP independently correlated with total body (r =0.33, P =0.03) and cardiac NE spillover (r =0.44, P =0.002). Sleep apnea severity bore no relationship to markers of sympathetic nerve activity. Conclusion—Total body and cardiac sympathetic nerve activity are elevated in CHF-CSA compared with CHF-OSA and CHF-N patients and are related to heart failure not apnea severity.

Predictors of early readmission or death in elderly patients with heart failure

BACKGROUND Contemporary heart failure (HF) patients are elderly and have a high rate of early rehospitalization or death, resulting in a high burden for both the patients and the health care system. Prior studies were focused on younger and less well-characterized patients. We aimed to identify predictors of early hospital readmission and death in elderly patients with HF. METHODS Patients with chronic HF taking part in the TIME-CHF study (n = 614, age 77 +/- 8 years, 41% female, left ventricular ejection fraction 35% +/- 13%) were evaluated with respect to predictors of hospital readmission or death 30 and 90 days after inclusion. Demographic, clinical, laboratory, echocardiographic, and social variables were obtained at baseline and included in a multivariable logistic regression analysis to identify predictors of early events. RESULTS The rate of hospital readmission or death was high at 30 (11%) and 90 days (26%). The reason for hospitalization was HF in 33%, other cardiovascular in 32%, and noncardiovascular in 45% of the cases, respectively. Predictors of readmission or death at 30 days were angina, lower systolic blood pressure, anemia, more extensive edema, higher creatinine levels, and dry cough; and at 90 days were coronary artery disease, prior pacemaker implantation, high jugular venous pressure, pulmonary rales, prior abdominal surgery, older age, and depressive symptoms. CONCLUSIONS Early hospital readmission or death was frequent among elderly HF patients. A very large proportion of readmissions were due to noncardiovascular causes. In addition to clinical signs of HF, comorbidities are important predictors of early events in elderly HF patients.

Drug-Eluting Stents Compared with Bare Metal Stents Improve Late Outcome after Saphenous Vein Graft but Not after Large Native Vessel Interventions

Objectives: To define long-term efficacy of different stent types in saphenous vein graft (SVG) interventions. Methods: In BASKET (Basel Stent Cost Effectiveness Trial), major adverse cardiac events (MACE), i.e. cardiac death, myocardial infarction and symptom-driven target vessel revascularization (TVR) were assessed after 18 months comparing drug-eluting stents (DES) versus bare metal stents (BMS), and SVG and large native vessels (≧3.0 mm). Results: Large vessel interventions were performed in 605 patients. Patients with SVG interventions (n = 47, 8%) were older and had more often hypertension, prior myocardial infarction, prior revascularization and multivessel disease and less frequent ST-elevation myocardial infarction than patients with large native vessel interventions (n = 558, 92%). Stent number and length were higher in SVG than in large native vessel interventions. Baseline characteristics were similar for DES and BMS. In SVG stenting, long-term outcome was better in DES- than in BMS-treated patients (MACE 21 vs. 62%, p = 0.007, mainly due to TVR 18 vs. 46%, p = 0.045), but for large native vessel stenting, no significant difference was noted (MACE: 13 vs. 16%, p = 0.40). Conclusions: Among patients with SVG disease, treatment with DES resulted in a better long-term outcome than treatment with BMS. In contrast, no DES benefit was found in similarly sized native vessels regarding MACE.

Which heart failure patients profit from natriuretic peptide guided therapy? A meta-analysis from individual patient data of randomized trials.

Previous analyses suggest that heart failure (HF) therapy guided by (N‐terminal pro‐)brain natriuretic peptide (NT‐proBNP) might be dependent on left ventricular ejection fraction, age and co‐morbidities, but the reasons remain unclear.

N-terminal pro brain natriuretic peptide-guided management in patients with heart failure and preserved ejection fraction: findings from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF)

To assess the effects of an NT‐proBNP‐guided medical management on 18‐month outcomes in patients with heart failure (HF) and preserved LVEF (HFpEF).

Incidence, clinical predictors, and prognostic impact of worsening renal function in elderly patients with chronic heart failure on intensive medical therapy

BACKGROUND Incidence, predictors, and prognostic impact of worsening renal function (WRF) in elderly patients with chronic heart failure (HF) undergoing intensive contemporary medical therapy are unknown. METHODS AND RESULTS In 566 patients (age 77 ± 8 years) included in the TIME-CHF, serum creatinine (sCr) was repeatedly measured up to 6 months. Worsening renal function was classified as increase in sCr by 0.2 to 0.3 (WRFI), 0.3 to 0.5 (WRFII), or ≥0.5 mg/dL (WRFIII) within the first 6 months. Outcome events were assessed for 18 months. RESULTS The incidence of WRF I, II, and III was 12%, 19%, and 22%, respectively. Worsening renal function III was associated with increased mortality (hazard ratio 1.98 [95% CI 1.27-3.07, P = .002] vs no WRF), whereas WRF I/II was not. History of renal failure, spironolactone treatment, higher baseline dose, and higher maximal increase in loop diuretic dose were independently associated with the occurrence of WRF III, whereas angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and β-blocker use and allocation to N-terminal pro-B-type natriuretic peptide-guided management were not. Worsening renal function III was an independent predictor of death, death or hospitalization, and death or HF hospitalization also after adjusting for baseline characteristics. CONCLUSIONS One fifth of elderly patients with chronic HF experienced WRF III on 6-month intensive HF treatment. These patients had higher mortality, whereas patients with smaller sCr rises did not. Occurrence of WRF III was associated with high doses of loop diuretics and spironolactone use but not with other treatments.

Frequency and Predictors of Hyperkalemia in Patients ≥60 Years of Age With Heart Failure Undergoing Intense Medical Therapy

Hyperkalemia is a concern in heart failure (HF), especially in older patients with co-morbidities. Previous studies addressing this issue have focused mainly on younger patients. This study was aimed at determining the frequency and predictors of hyperkalemia in older patients with HF undergoing intense medical therapy. Frequency and predictors of hyperkalemia were defined in patients (n = 566) participating in the Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure, in which patients ≥60 years of age were randomized to a standard versus an intensified N-terminal brain natriuretic peptide-guided HF therapy. During an 18-month follow-up 76 patients (13.4%) had hyperkalemia (≥5.5 mmol/L) and 28 (4.9%) had severe hyperkalemia (≥6.0 mmol/L). Higher baseline serum potassium (odds ratio [OR] 2.92 per mmol/L), baseline creatinine (OR 1.11 per 10 μmol/L), gout (OR 2.56), New York Heart Association (NYHA) class (compared to NYHA class II, IV OR 3.08), higher dosage of spironolactone at baseline (OR 1.20 per 12.5 mg/day), and higher dose changes of spironolactone (compared to no dose change: 12.5 mg, OR 1.45; 25 mg, OR 2.52; >25 mg, OR 3.24) were independent predictors for development of hyperkalemia (p <0.05 for all comparisons). In conclusion, hyperkalemia is common in patients ≥60 years of age with HF undergoing intense medical therapy. Risk is increased in patients treated with spironolactone, in addition to patient-specific risk factors such as chronic kidney disease, higher serum potassium, advanced NYHA class, and gout. Careful surveillance of serum potassium and cautious use of spironolactone in patients at risk may help to decrease the incidence of potentially hazardous complications caused by hyperkalemia.