Pharmacological therapy for chronic heart failure.

Pharmacotherapy of chronic heart failure with reduced ejection fraction (HFrEF) is based on convincing evidence of both, the efficacy and the safety of drugs we are using. This evidence was obtained in big and carefully controlled randomised morbidity/mortality trials; therefore we are talking about evidence-based medicine. The basis for the pharmacological treatment is inhibition of pathologically long-term activated neurohumoral systems, mainly of the sympatoadrenal one by betablockers as well as of the renin-angiotensin-aldosterone one by ACE inhibitors/sartans and by mineralocorticoid receptor antagonists. The new dual inhibitor sacubitril/valsartan should be considered as more effective substitute of ACE inhibitors/sartans in all stabilised patients. Addition of ivabradin could also be usefull in indicated patients. The role of digoxin had diminished much. At present it is used especially for rate control in heart failure patients with atrial tachyfibrillation. All symptomatic patients should be treated by diuretics. The treatment of heart failure is very complex. The pharmacotherapy has to be complemented by relevant lifestyle changes and in selected patients also by devices and/or surgical therapy including heart transplantation. Key words: betablockers - chronic heart failure - ivabradin - pharmacotherapy - RAAS inhibitors - sacubitril/valsartan.

European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions.

AIMS: The European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT-R) was set up with the aim of describing the clinical epidemiology and the 1-year outcomes of patients with heart failure (HF) with the added intention of comparing differences between participating countries. METHODS AND RESULTS: The ESC-HF-LT-R is a prospective, observational registry contributed to by 211 cardiology centres in 21 European and/or Mediterranean countries, all being member countries of the ESC. Between May 2011 and April 2013 it collected data on 12 440 patients, 40.5% of them hospitalized with acute HF (AHF) and 59.5% outpatients with chronic HF (CHF). The all-cause 1-year mortality rate was 23.6% for AHF and 6.4% for CHF. The combined endpoint of mortality or HF hospitalization within 1 year had a rate of 36% for AHF and 14.5% for CHF. All-cause mortality rates in the different regions ranged from 21.6% to 36.5% in patients with AHF, and from 6.9% to 15.6% in those with CHF. These differences in mortality between regions are thought reflect differences in the characteristics and/or management of these patients. CONCLUSION: The ESC-HF-LT-R shows that 1-year all-cause mortality of patients with AHF is still high while the mortality of CHF is lower. This registry provides the opportunity to evaluate the management and outcomes of patients with HF and identify areas for improvement.

[Controversies accumulated around betablockers]. / Kontroverze kolem betablokátoru.

Betablockers are one of the most successful drug classes in cardiology. They have many indications - starting with treatment of arterial hypertension, continuing with secondary prevention post myocardial infarction up to the treatment of heart failure with reduced ejection fraction. Recently, many analysis and information were published which are questioning yet unshakable role of betablockers in some cardiovascular diagnosis. This review article summarizes the controversies, which have accumulated around betablockers in the treatment of hypertension, secondary prevention of coronary artery disease, perioperative administration in patients undegoing non-cardiac surgery and treatment of heart failure with reduced ejection fraction. Some of these controversies already led to guidelines modifications, other will probably lead to guidelines changes in near future.Key words: arterial hypertension - betablockers - heart failure - perioperative care - secondary prevention.

[Chronic heart failure]. / Chronické srdecní selhání.

Incidence of chronic heart failure (HF) is increasing steadily in all developed countries, predominantly due to population ageing. The prevalence of HF in population is 1-2%, reaching up to 10% in higher age categories. At present HF is classified according to left ventricular ejection fraction (EF) value to HF with reduced EF (formerly systolic HF) and HF with preserved EF (formerly diastolic HF). Coronary artery disease dominates in the aetiology of HF with reduced EF (about 70%), especially status post myocardial infarction. Pathophysiology of HF with preserved EF is very complex and still not fully understood. Multiple comorbidities play an important role, especially hypertension and diabetes mellitus. HF with preserved EF represents about half of all HF cases and its rate is slowly increasing. Morbidity expressed as hospitalization rate is comparable in patients with both types of HF, whereas mortality is a little bit lower in patients with HF with preserved EF. But in patients with HF and preserved EF the prevailing causes of both, the hospitalizations and the deaths are non-cardiovascular.Diagnosis of HF is relatively simple in fully manifested cases, but it could be a problem in milder forms especially of the HF with preserved EF in elderly patients with multiple comorbidities. For the definite diagnosis of HF the patient has to have typical symptoms and clinical signs as well as objectively documented left ventricular dysfunction, usually by echocardiography. According to the EF value the type of HF is determined. In HF with preserved EF an evidence of a structural heart impairment and/or left ventricular diastolic dysfunction is also necessary. Plasma levels of natriuretic peptides could be helpful for determination of correct diagnosis, particularly in untreated patients. Basic examination of patients with suspected HF is completed by ECG and some laboratory parameters (e.g. renal function, ions, red blood count).Treatment of HF with reduced EF is based on evidence from many clinical trials. It is complex and consists on non-pharmacological interventions, pharmacotherapy (ACE inhibitors, sartans, betablockers, mineralocortikoid receptor blockers, in specific situations also ivabradine and digoxin), surgery and devices. There is no evidence-based treatment for HF with preserved EF, therefore it still remains empiric.

[Treatment of heart failure in diabetic patients]. / Lécba srdecního selhání u diabetiku

Heart failure occurs in diabetic patients and vice versa, among patients with heart failure is high prevalence of diabetes mellitus. Treatment of heart failure in diabetics is not substantially different from the treatment of heart failure in non-diabetic patients. It is based on ACE-inhibitors, beta-blockers and mineralocorticoid receptor blockers. In advanced heart failure the treatment with various devices reaches importance, for example biventricular pacing for cardiac resynchronization. Recently, it has been discussed the question of long-term cardiovascular safety of hypoglycaemic drugs. Older anti-diabetic agents such as insulin, metformin, and sulfonylurea are considered to be cardiovascular safe. However, rosiglitazone from thiazolidinedione class increases incidence of cardiovascular events, resulting in cancellation of its registration in Europe and its considerably limited use in the United States. Therefore, cardiovascular safety is tested very carefully in clinical trials in new anti-diabetic agents that affect incretin system. Recently, saxagliptin has shown to increase incidence of heart failure in diabetic patients.

Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry.

AIMS: To evaluate how recommendations of European guidelines regarding pharmacological and non-pharmacological treatments for heart failure (HF) are adopted in clinical practice. METHODS AND RESULTS: The ESC-HF Long-Term Registry is a prospective, observational study conducted in 211 Cardiology Centres of 21 European and Mediterranean countries, members of the European Society of Cardiology (ESC). From May 2011 to April 2013, a total of 12,440 patients were enrolled, 40.5% with acute HF and 59.5% with chronic HF. Intravenous treatments for acute HF were heterogeneously administered, irrespective of guideline recommendations. In chronic HF, with reduced EF, renin-angiotensin system (RAS) blockers, beta-blockers, and mineralocorticoid antagonists (MRAs) were used in 92.2, 92.7, and 67.0% of patients, respectively. When reasons for non-adherence were considered, the real rate of undertreatment accounted for 3.2, 2.3, and 5.4% of the cases, respectively. About 30% of patients received the target dosage of these drugs, but a documented reason for not achieving the target dosage was reported in almost two-thirds of them. The more relevant reasons for non-implantation of a device, when clinically indicated, were related to doctor uncertainties on the indication, patient refusal, or logistical/cost issues. CONCLUSION: This pan-European registry shows that, while in patients with acute HF, a large heterogeneity of treatments exists, drug treatment of chronic HF can be considered largely adherent to recommendations of current guidelines, when the reasons for non-adherence are taken into account. Observations regarding the real possibility to adhere fully to current guidelines in daily clinical practice should be seriously considered when clinical practice guidelines have to be written.

Organization of heart failure management in European Society of Cardiology member countries: survey of the Heart Failure Association of the European Society of Cardiology in collaboration with the Heart Failure National Societies/Working Groups.

AIMS: The aim of this document was to obtain a real-life contemporary analysis of the demographics and heart failure (HF) statistics, as well as the organization and major activities of the Heart Failure National Societies (HFNS) in European Society of Cardiology (ESC) member countries. METHODS AND RESULTS: Data from 33 countries were collected from HFNS presidents/representatives during the first Heart Failure Association HFNS Summit (Belgrade, Serbia, 29 October 2011). Data on incidence and/or prevalence of HF were available for 22 countries, and the prevalence of HF ranged between 1% and 3%. In five European and one non-European ESC country, heart transplantation was reported as not available. Natriuretic peptides and echocardiography are routinely applied in the management of acute HF in the median of 80% and 90% of centres, respectively. Eastern European and Mediterranean countries have lower availability of natriuretic peptide testing for acute HF patients, compared with other European countries. Almost all countries have organizations dealing specifically with HF. HFNS societies for HF patients exist in only 12, while in 16 countries HF patient education programmes are active. Most HFNS reported that no national HF registry exists in their country. Fifteen HFNS produced national HF guidelines, while 19 have translated the ESC HF guidelines. Most HFNS (n = 23) participated in the organization of the European HF Awareness Day. CONCLUSION: This document demonstrated significant heterogeneity in the organization of HF management, and activities of the national HF working groups/associations. High availability of natriuretic peptide and echocardiographic measurements was revealed, with differences between developed countries and countries in transition.

Post hoc analysis of the Cluster Randomized Usual Care versus Caduet Investigation Assessing Long-term risk (CRUCIAL) trial.

OBJECTIVE: A proactive, multifactorial intervention strategy incorporating single-pill amlodipine/atorvastatin (SPAA) (5-10/10 mg up-titrated to 5-10/20 mg, where approved) is more effective than physician's usual care (UC) for reducing calculated 10 year coronary heart disease (CHD) risk, in patients with hypertension and additional risk factors (CRUCIAL trial: Curr Med Res Opin 2011;27:821--33). As SPAA combinations containing atorvastatin 20 mg are not approved in some countries, this post hoc analysis investigated the efficacy and safety of a proactive intervention strategy incorporating low-dose SPAA (5/10 or 10/10 mg) only (low-dose PI) versus UC. METHODS: Of 1461 CRUCIAL participants (35-79 years; hypertension and ≥3 additional risk factors; no CHD; total cholesterol ≤6.5 mmol/L), 105 were prescribed SPAA containing 20 mg atorvastatin and excluded. The primary endpoint was difference between treatment arms in Framingham 10 year CHD risk after 52 weeks; secondary assessments included difference in calculated CHD risk at Week 16; SCORE cardiovascular mortality (Week 16 and 52); blood pressure (BP)/lipid parameters; adverse events (AEs). RESULTS: Baseline BP (149.2/89.2 vs. 144.3/86.5 mmHg) and calculated CHD risk (19.6% vs. 18.1%) were higher for low-dose PI (n = 655) versus UC (n = 657) patients. Least-squares mean treatment difference (low-dose PI vs. UC) in calculated 10 year CHD risk was -26.8 (95% CI: -31.7, -22.0; p < 0.001) after 52 weeks' follow-up and -24.8 (-29.8, -19.9; p < 0.001) after 16 weeks' follow-up. Treatment difference in SCORE mortality was -20.1 (-24.7, -15.6; p < 0.001) and -22.4 (-26.8, -18.0; p < 0.001) after 16 and 52 weeks' follow-up. Risk calculations are surrogate endpoints and may not translate into actual reductions in cardiovascular events. Overall, 49.1% (low-dose PI) and 44.0% (UC) reported AEs. CONCLUSION: A proactive, multifactorial approach to cardiovascular management based on low-dose SPAA led to statistically significant improvements in calculated 10 year CHD risk versus physician's UC, comparable to that reported in the full CRUCIAL trial. These data will inform healthcare providers in countries where SPAA (5/10 or 10/10 mg) only are licensed.

Left ventricle remodeling in men with moderate to severe volume-dependent hypertension.

We evaluated the influence of increased intravascular volume on the heart anatomy in salt-sensitive types of hypertension, represented by primary aldosteronism (PA) and low-renin essential hypertension (LREH). Echocardiography was performed in 128 males with moderate to severe or resistant hypertension: 44 patients had PA, 40 patients had LREH and 44 patients had normal-renin essential hypertension (NREH). Groups were comparable in demographic characteristics, blood pressure, duration of hypertension and previous antihypertensive treatment. Patients with PA and LREH, in comparison with NREH patients, showed both greater end-systolic (37.6±5.4 and 35.6±4.5 vs 32.6±4.4 mm, p<0.001 and p<0.05) and end-diastolic (56.1±4.5 and 54.0±4.8 vs 50.4±5.1 mm; p<0.001 and p<0.01) left ventricle (LV) diameter. There were no significant differences either in LV wall thicknesses or LV mass, although a higher percentage of patients with PA and LREH met the criteria of eccentric hypertrophy (p<0.001 and p<0.05 respectively). Aldosterone concentration was positively related to LV cavity dimensions, whether wall thicknesses were rather associated with blood pressure levels. In conclusion, plasma volume overload was identified as an important factor influencing LV remodeling in PA and LREH, whether due to excessive aldosterone levels in PA or other pathophysiological mechanisms.

Effects of statin therapy according to plasma high-sensitivity C-reactive protein concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): a retrospective analysis.

BACKGROUND: We examined whether the antiinflammatory action of statins may be of benefit in heart failure, a state characterized by inflammation in which low cholesterol is associated with worse outcomes. METHODS AND RESULTS: We compared 10 mg rosuvastatin daily with placebo in patients with ischemic systolic heart failure according to baseline high sensitivity-C reactive protein (hs-CRP) <2.0 mg/L (placebo, n=779; rosuvastatin, n=777) or > or = 2.0 mg/L (placebo, n=1694; rosuvastatin, n=1711). The primary outcome was cardiovascular death, myocardial infarction, or stroke. Baseline low-density lipoprotein was the same, and rosuvastatin reduced low-density lipoprotein by 47% in both hs-CRP groups. Median hs-CRP was 1.10 mg/L in the lower and 5.60 mg/L in the higher hs-CRP group, with higher hs-CRP associated with worse outcomes. The change in hs-CRP with rosuvastatin from baseline to 3 months was -6% in the low hs-CRP group (27% with placebo) and -33.3% in the high hs-CRP group (-11.1% with placebo). In the high hs-CRP group, 548 placebo-treated (14.0 per 100 patient-years of follow-up) and 498 rosuvastatin-treated (12.2 per 100 patient-years of follow-up) patients had a primary end point (hazard ratio of placebo to rosuvastatin, 0.87; 95% confidence interval, 0.77 to 0.98; P=0.024). In the low hs-CRP group, 175 placebo-treated (8.9 per 100 patient-years of follow-up) and 188 rosuvastatin-treated (9.8 per 100 patient-years of follow-up) patients experienced this outcome (hazard ratio, 1.09; 95% confidence interval, 0.89 to 1.34; P>0.2; P for interaction=0.062). The numbers of deaths were as follows: 581 placebo-treated (14.1 per 100 patient-years of follow-up) and 532 rosuvastatin-treated (12.6 per 100 patient-years) patients in the high hs-CRP group (hazard ratio, 0.89; 95% confidence interval, 0.79 to 1.00; P=0.050) and 170 placebo-treated (8.3 per 100 patient-years) and 192 rosuvastatin-treated (9.7 per 100 patient-years) patients in the low hs-CRP group (hazard ratio, 1.17; 95% confidence interval, 0.95 to 1.43; P=0.14; P for interaction=0.026). CONCLUSIONS: In this retrospective hypothesis-generating study, we found a significant interaction between hs-CRP and the effect of rosuvastatin for most end points whereby rosuvastatin treatment was associated with better outcomes in patients with hs-CRP > or = 2.0 mg/L. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Rosuvastatin in older patients with systolic heart failure.

BACKGROUND: Patients with systolic heart failure have generally been excluded from statin trials. Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients. METHODS: A total of 5011 patients at least 60 years of age with New York Heart Association class II, III, or IV ischemic, systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per day. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included death from any cause, any coronary event, death from cardiovascular causes, and the number of hospitalizations. RESULTS: As compared with the placebo group, patients in the rosuvastatin group had decreased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P<0.001) and of high-sensitivity C-reactive protein (difference between groups, 37.1%; P<0.001). During a median follow-up of 32.8 months, the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.83 to 1.02; P=0.12), and 728 patients and 759 patients, respectively, died (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.31). There were no significant differences between the two groups in the coronary outcome or death from cardiovascular causes. In a prespecified secondary analysis, there were fewer hospitalizations for cardiovascular causes in the rosuvastatin group (2193) than in the placebo group (2564) (P<0.001). No excessive episodes of muscle-related or other adverse events occurred in the rosuvastatin group. CONCLUSIONS: Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. The drug did not cause safety problems. (ClinicalTrials.gov number, NCT00206310.)

Recurrent peripheral arterial embolism from metastatic lung choriocarcinoma--a case report.

A patient with choriocarcinoma, most likely of ovarian origin, with lung metastasis is presented. The disease manifested itself by recurrent embolism into the peripheral arteries. Literature on this topic is reviewed.

Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials.

BACKGROUND: Patients with symptomatic chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) have a high risk of death and hospitalization for CHF deterioration despite therapies with angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and even an aldosterone antagonist. To determine whether the angiotensin-receptor blocker (ARB) candesartan decreases cardiovascular mortality, morbidity, and all-cause mortality in patients with CHF and depressed LVEF, a prespecified analysis of the combined Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) low LVEF trials was performed. CHARM is a randomized, double-blind, placebo-controlled, multicenter, international trial program. METHODS AND RESULTS: New York Heart Association (NYHA) class II through IV CHF patients with an LVEF of < or =40% were randomized to candesartan or placebo in 2 complementary parallel trials (CHARM-Alternative, for patients who cannot tolerate ACE inhibitors, and CHARM-Added, for patients who were receiving ACE inhibitors). Mortality and morbidity were determined in 4576 low LVEF patients (2289 candesartan and 2287 placebo), titrated as tolerated to a target dose of 32 mg once daily, and observed for 2 to 4 years (median, 40 months). The primary outcome (time to first event by intention to treat) was cardiovascular death or CHF hospitalization for each trial, with all-cause mortality a secondary end point in the pooled analysis of the low LVEF trials. Of the patients in the candesartan group, 817 (35.7%) experienced cardiovascular death or a CHF hospitalization as compared with 944 (41.3%) in the placebo group (HR 0.82; 95% CI 0.74 to 0.90; P<0.001) with reduced risk for both cardiovascular deaths (521 [22.8%] versus 599 [26.2%]; HR 0.84 [95% CI 0.75 to 0.95]; P=0.005) and CHF hospitalizations (516 [22.5%] versus 642 [28.1%]; HR 0.76 [95% CI 0.68 to 0.85]; P<0.001). It is important to note that all-cause mortality also was significantly reduced by candesartan (642 [28.0%] versus 708 [31.0%]; HR 0.88 [95% CI 0.79 to 0.98]; P=0.018). No significant heterogeneity for the beneficial effects of candesartan was found across prespecified and subsequently identified subgroups including treatment with ACE inhibitors, beta-blockers, an aldosterone antagonist, or their combinations. The study drug was discontinued because of adverse effects by 23.1% of patients in the candesartan group and 18.8% in the placebo group; the reasons included increased creatinine (7.1% versus 3.5%), hypotension (4.2% versus 2.1%), and hyperkalemia (2.8% versus 0.5%), respectively (all P<0.001). CONCLUSIONS: Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF < or =40% when added to standard therapies including ACE inhibitors, beta-blockers, and an aldosterone antagonist. Routine monitoring of blood pressure, serum creatinine, and serum potassium is warranted.

Effect of folic acid on fenofibrate-induced elevation of homocysteine and cysteine.

BACKGROUND: An elevated total plasma homocysteine (tHcy) level is considered to be an independent risk factor for atherosclerosis. It has been reported that lipid-lowering therapy with fibric acid derivatives (fibrates) increases tHcy and total plasma cysteine (tCys) levels. The aim of this study was to determine whether therapy with folic acid, a potent tHcy-lowering agent, could modify the fenofibrate-induced elevation of plasma aminothiols. METHODS: Patients with combined hyperlipidemia (n = 37) were randomized to receive 9 weeks of treatment with micronized fenofibrate 200 mg/day (F group) or fenofibrate 200 mg/day plus folic acid 10 mg/every other day (F+F group). tCys and tHcy levels were determined before and after the therapy with high performance liquid chromatography. RESULTS: The tHcy level increased significantly in the F group by 51.3% and in the F+F group by 14.6% (between-group difference P =.001). Total plasma cysteine (tCys) increased similarly after both treatments (P =.72). The serum creatinine level increased in the F group by 20.7% and in F+F group only by 9.8% (P =.04). The increase of tHcy level in F group correlated with an increase of tCys and creatinine levels (r = 0.74 and 0.64, respectively). The effects on the lipid profile did not differ by treatment group. CONCLUSIONS: Folic acid effectively reduces the fenofibrate-induced elevation of tHcy and creatinine, but it does not affect the elevation of the tCys. Folic acid has neutral effect on the lipid-lowering action of fenofibrate. Clinical efficacy of fenofibrate might be improved by folic acid coadministration.

Nitroglycerin induced syncope occurs in subjects with delayed phase shift of baroreflex action.

Nitroglycerin (NTG) administration occasionally leads to syncope due to severe hypotension and bradycardia. This reaction resembles neurocardiogenic syncope but it may occur when the patient is in the supine position. To address the possible role of prevailing autonomic tone and baroreflex control in precipitation of NTG induced syncope, continuous noninvasive blood pressure and an ECG were taken shortly before NTG application in the supine position. Frequency-domain measures of heart rate variability (HRV) and noninvasive indices of baroreflex were compared between subjects who did (n = 6) and did not (n = 41) develop syncope after NTG. Both groups differed only in the phase shift (P(CR)) between oscillations of blood pressure and heart rate during controlled respiration (0.1 Hz). P(CR) was significantly delayed in subjects who developed syncope than in controls (- 99.3+/-14.1 vs -65.5+/-27.0 degrees, P = 0.002). Thus, subjects with prolonged P(CR) are prone to NTG induced syncope because of increased lagging and, consequently, less stable baroreflex control.