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.)

A Narrative Review and Expert Panel Recommendations on Dyslipidaemia Management After Acute Coronary Syndrome in Countries Outside Western Europe and North America.

Patients who have experienced an acute coronary syndrome (ACS) are at very high risk of recurrent atherosclerotic cardiovascular disease (CVD) events. Dyslipidaemia, a major risk factor for CVD, is poorly controlled post ACS in countries outside Western Europe and North America, despite the availability of effective lipid-modifying therapies (LMTs) and guidelines governing their use. Recent guideline updates recommend that low-density lipoprotein cholesterol (LDL-C), the primary target for dyslipidaemia therapy, be reduced by ≥ 50% and to < 1.4 mmol/L (55 mg/dL) in patients at very high risk of CVD, including those with ACS. The high prevalence of CVD risk factors in some regions outside Western Europe and North America confers a higher risk of CVD on patients in these countries. ACS onset is often earlier in these patients, and they may be more challenging to treat. Other barriers to effective dyslipidaemia control include low awareness of the value of intensive lipid lowering in patients with ACS, physician non-adherence to guideline recommendations, and lack of efficacy of currently used LMTs. Lack of appropriate pathways to guide follow-up of patients with ACS post discharge and poor access to intensive medications are important factors limiting dyslipidaemia therapy in many countries. Opportunities exist to improve attainment of LDL-C targets by the use of country-specific treatment algorithms to promote adherence to guideline recommendations, medical education and greater prioritisation by healthcare systems of dyslipidaemia management in very high risk patients.

The therapeutic management of South African dyslipidaemic patients at very high cardiovascular risk (CARDIO TRACK): a cross-sectional study.

BACKGROUND: Dyslipidaemia is a major modifiable risk factor for atherosclerotic cardiovascular disease. At the time the study was conducted, guidelines recommended a low-density lipoprotein cholesterol (LDL-C) target of less than 1.8 mmol/l and a reduction of at least 50% if the baseline LDL-C was between 1.8 and 3.5 mmol/l in patients with either very high cardiovascular risk or established atherosclerosis. In South Africa, there is a paucity of data on attainment of LDL-C goal in patients with very high cardiovascular risk who are on maximum tolerated statin with or without ezetimibe. OBJECTIVE: The aim was to assess the percentage of very high cardiovascular risk South African patients with dyslipidaemia not reaching an LDL-C goal of less than 1.8 mmol/l, despite maximum tolerated statin with or without ezetimibe. METHODS: This was a multi-centre, observational, cross-sectional study conducted at 15 private healthcare sector sites and one public sector site. Adults (> 18 years) with very high cardiovascular risk of familial hypercholesterolaemia receiving stable, maximum-tolerated statin therapy for at least four weeks prior to their latest lipid profile were enrolled into the study, and electronic case report forms were completed after written informed consent was provided. LDL-C goal attainment was modelled, first assuming an increase in the statin dose to the registered maximum, followed by the addition of ezetimibe or a PCSK9-inhibitor. RESULTS: In total, 507 patients were screened, of whom 492 were eligible for study participation. One patient was excluded from the analysis because of a missing LDL-C value. Most participants were male (male 329, 67%; female 162, 33%). Most patients were either obese (223, 46.0%) or overweight (176, 36.3%). Hypertension and diabetes mellitus were frequent co-morbidities and were found in 381 (77.6%) and 316 (64.4%) patients, respectively. Eighty (16.3%) patients reported current smoking. Only 68 (13.8%) patients were taking ezetimibe in addition to a statin. Reasons for not using ezetimibe included no requirement for ezetimibe in the opinion of the treating physician (229, 48.7%), cost (149, 31.7%), Physician's choice (39, 8.3%), or other (53, 11.3%). Only 161 (32.8%) of the patients attained their goal LDL-C level. In our modelling analysis, increasing the statin dose to the registered maximum and adding ezetimibe brought an additional 34.5% of patients to goal, while adding a PCSK9-inhibitor, irrespective of any other changes to lipid-lowering therapy brought over 90% of not-at-goal patients to goal. CONCLUSIONS: Most study participants were not at LDL-C goal despite maximum-tolerated statin, highlighting the need for treatment intensification in this high-risk population. Although intensifying treatment by adding a PCSK9-inhibitor brought more patients to goal, the initial addition of ezetimibe would be more reasonable, given the cost of PCSK9-inhibitors.

PCSK9 Inhibitors: From Nature's Lessons to Clinical Utility.

BACKGROUND: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of non-statin lipid lowering therapy that reduce LDL-cholesterol by 50 - 60%. PCSK9 inhibitors decrease LDL-cholesterol by preventing intracellular degradation of LDL receptors; subsequently, a greater number of LDL-receptors are available on the cell surface to extract circulating LDL. OBJECTIVE: To describe the origins of PCSK9 inhibitors and their current use in clinical practice. METHODS: We performed a narrative review of the PCSK9 inhibitor class of drugs. RESULTS: Current data indicate that PCSK9 inhibitors effectively reduce LDL-cholesterol and are well tolerated and safe. PCSK9 inhibitors have also been shown to reduce cardiovascular event rates in patients with stable atherosclerotic cardiovascular disease and in patients with a recent (up to one year) acute coronary syndrome. Given the costs, chronicity of the treatment and the potential budget impact, PCSK9 inhibitors are often limited to patients with the highest absolute risk for major adverse cardiovascular events despite optimal treatment with high-intensity statin and ezetimibe. CONCLUSION: PCSK9 inhibitors have a favorable safety, efficacy and tolerability profile. Postmarketing safety surveillance and real-world studies are needed to further support the long-term safety profile of this class of medicine.

Marfan syndrome: a case report and pictorial essay.

We report a case of Marfan syndrome (MFS) in a South African patient, which is extraordinary because of the large constellation of clinical, radiological and vascular anomalies in a single patient. A literature search from 1950 to date did not show a similar report of such extensive clinical characteristics of MFS.

Baseline Characteristics of Patients With Heart Failure and Preserved Ejection Fraction in the PARAGON-HF Trial.

BACKGROUND: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. METHODS AND RESULTS: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), ß-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. CONCLUSIONS: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Association Between Hyperuricemia and Major Adverse Cardiac Events in Patients with Acute Myocardial Infarction.

BACKGROUND: To investigate the association between hyperuricemia and major adverse cardiac events (MACE) in patients with acute myocardial infarction (AMI). METHODS: Consecutive patients admitted with AMI to the Coronary Care Unit at R. K. Khan Hospital (Durban, South Africa) between the years 2006 and 2014 were included. Demographic data, including clinical and biochemical information stored in an electronic database, were obtained from all patients. RESULTS: A total of 2683 patients were studied, of whom 65% were males. The mean age of the participants was 57.1 ± 11.5 years, with 79% presenting with ST elevation myocardial infarction. Sixty-one percent were smokers, 59% had diabetes mellitus, 52% had hypertension, and 58% presented with a family history of premature coronary artery disease. Twenty-six percent (n = 690) had hyperuricemia, were older (59 ± 12.1 vs. 56.5 ± 11.2 years) and more likely to present with hypertension (P < 0.001), lower ejection fraction (P < 0.001), and higher median creatinine levels (P < 0.001). A significantly greater proportion of patients with hyperuricemia experienced MACE (45% vs. 30%, P < 0.001). In both sexes, considerable heterogeneity for risk factors and clinical events was noted in individuals with hyperuricemia. Multivariable analyses for risk factors associated with mortality suggest that hyperuricemia conferred a significantly increased risk of mortality after adjustment [odds ratio (OR) 1.7 (95% confidence interval 1.0-2.8); P = 0.042]. A significant increasing risk trend for MACE was observed for increasing tertiles of serum uric acid concentrations above normal (P < 0.001), particularly for cardiac failure (P < 0.001) and death (P = 0.006). CONCLUSIONS: Hyperuricemia is significantly associated with hypertension, renal dysfunction, MACE, and independently confers a higher risk of mortality in patients with AMI. Significant heterogeneity was found by gender for risk factors and clinical events in individuals with hyperuricemia. A graded increase was demonstrated in the risk of MACE, particularly for cardiac failure and death, by increasing tertiles of hyperuricemia.

Lipid profiles and associated gene polymorphisms in young Asian Indian patients with acute myocardial infarction and the metabolic syndrome.

BACKGROUND: The objective of this study was to examine the association between serum lipid levels and the metabolic syndrome, together with polymorphisms in lipid-associated genes, in young Asian Indians with acute myocardial infarction (AMI). METHODS: The study population comprised 492 patients who were 45 years old or younger. We assessed lipid levels and the frequencies of the cholesteryl ester transfer protein (CETP) Taq-1 B, lipoprotein lipase (LPL)S447X, -93 T/G, apolipoprotein B (APO B) 96bp ins/del, lipoprotein(a) (LP[a]) pentanucleotide repeat, and apolipoprotein E (APO) E epsilon 2/3/4 polymorphisms in relation to the metabolic syndrome using both National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and International Diabetes Federation (IDF) definitions. RESULTS: The metabolic syndrome as defined by the NCEP ATP III criteria was found in 301 (61%) patients and in 295 (60%) patients according to the IDF criteria. Hypercholesterolemia (64.5%), hypertriglyceridaemia (78.7%), low high-density lipoprotein cholesterol (HDL-C) (70.1%), and raised non-HDL-C (68.0%) occurred significantly more frequently in patients with the metabolic syndrome defined by the NCEP ATP III criteria. Similar results were observed for the IDF definition. A significant relationship with the LPL -93 T/G polymorphism was found, with the minor G allele occurring more frequently in patients defined by the NCEP ATP III criteria (odds ratio [OR] 2.72; 95% confidence interval [CI] 1.07-8.16; P = 0.023). The X allele of the LPL S447X polymorphism was observed less frequently in metabolic syndrome patients (OR 0.52; 95% CI 0.34-0.78; P = 0.0009). Several genotypes, including the LPL S447X, APO E3/E3, and the CETP Taq1 B2B2, were associated with favorable lipid profiles. CONCLUSION: Dyslipidemia occurred with similar frequency in young Asian Indian patients with AMI and the metabolic syndrome, irrespective of the definition used. Significant associations were observed between LPL gene polymorphisms and the metabolic syndrome. Several lipid-associated genotypes exerted a favorable effect on lipid profiles.

Plasma concentration of amino-terminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin: a report from CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure).

OBJECTIVES: We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective. BACKGROUND: Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile. METHODS: In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke. RESULTS: Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin. CONCLUSIONS: Patients with heart failure due to ischemic heart disease who have NT-proBNP values <103 pmol/l (868 pg/ml) may benefit from rosuvastatin.

Genetic variants associated with insulin resistance and metabolic syndrome in young Asian Indians with myocardial infarction.

BACKGROUND: The objective of this study was to assess whether an association exists between the metabolic syndrome and polymorphisms in genes involved in insulin resistance in young Asian Indian patients presenting with acute myocardial infarction (AMI). METHODS: The study population comprised 467 patients who were 45 years or younger. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and the International Diabetes Federation (IDF) definitions were used to assess the prevalence of metabolic syndrome. We examined the genotype and allele frequencies of the IRS-I G972R, PPAR-gamma P12A, KCNJ11 E23K, and TNF-alpha -308G/A polymorphisms in relation to the metabolic syndrome determined by both definitions. RESULTS: The metabolic syndrome as defined by the NCEP ATP III criteria was found in 282 (60.4%) patients, and in 278 (59.5%) patients according to the IDF criteria. This gave only a moderate level of agreement of 79% between the two definitions (Cohen's kappa = 0.554). No association was found between the IRS-I G972R, PPAR-gamma P12A, and KCNJ11 E23K, or TNF-alpha -308G/A polymorphic variants and the metabolic syndrome, or its components, for either definition. CONCLUSION: Although the metabolic syndrome is a common finding in young Asian Indian patients with AMI, there was only a moderate level of agreement between the NCEP ATP III and IDF definitions of the syndrome. Our findings do not support a role for any of the polymorphic variant alleles in the four insulin resistance-related genes examined in the etiology of insulin resistance and reinforces the notion of a multifactorial etiology for the metabolic syndrome.

The role of echocardiography and its comparison with NT-proBNP measurements in patients with acute myocardial infarction.

BACKGROUND: This study investigated the use of echocardiography in the early detection of regional wall motion abnormalities (RWMA) in patients presenting with acute myocardial infarction (AMI). The relationship between RWMA and mechanical complications, as assessed by two-dimensional echocardiography, and admission levels of amino terminal fragment of pro-brain natriuretic peptide (NT- proBNP) was also examined. MATERIAL/METHODS: The study population comprised 226 patients admitted to hospital with a diagnosis of AMI. Echocardiography and NT-proBNP measurements were performed on all patients. RESULTS: Sixty-eight percent of the patients with AMI were found to have RWMA on echocardiography. Significantly more patients had RWMA within any given range of ejection fraction (EF) (p<0.001), but this difference was most pronounced in those with left ventricular (LV) dysfunction. Mitral regurgitation was the most common complication (48%) seen on echocardiography. The majority of patients (84%) had elevated NT-proBNP levels on admission; this was evident in all categories of EF (p=0.003). In those with normal EF on echocardiography (58%), more patients had elevated levels regardless of the presence of RWMA. CONCLUSIONS: This study showed that echocardiography is useful in the detection of RWMA in the early stages of AMI. No significant relationship was demonstrated between NT-proBNP levels and RWMA in patients with normal or abnormal LV function. Admission plasma NT-proBNP may, however, be considered as an additional marker in the diagnosis of AMI, especially in those without RWMA.

Haemostatic gene polymorphisms in young indian asian subjects with acute myocardial infarction.

BACKGROUND: The relationship between haemostatic gene polymorphisms and arterial disease remains unclear. Much of the evidence gathered so far has been obtained from small heterogeneous studies, resulting in inconsistencies. This study focuses on the South African Indian population which not only represents the largest Indian population outside the Indian subcontinent, but also constitutes a genetically discrete group in whom a high incidence of coronary heart disease occurs. MATERIAL/METHODS: We investigated the relationship between polymorphisms in the Factor V (Leiden), prothrombin (20210 GgA) and thrombomodulin (Ala455Val) genes in patients with a myocardial infarction (MI) <45 years of age (n=195) and in unaffected siblings (n=107) and unrelated healthy race-matched individuals drawn from the same community (n=300). RESULTS: The Factor V Leiden mutation was found to occur with a frequency of less than 1%, while the prothrombin 20210 GgA polymorphism was not observed in any of the individuals in this study. In contrast, the variant thrombomodulin Val allele occurred with a frequency similar to that reported in Caucasians. The frequency of this allele in both patients with MI and their siblings was marginally higher than in healthy controls, but the difference did not reach statistical significance. However, in patients who smoked, the thrombomodulin variant allele occurred significantly more frequently than in the non-smoking group (p=0.044). CONCLUSIONS: The Leiden Factor V and prothrombin 20210 GgA polymorphisms have no value in disease association studies in the Indian Asian population. In smokers, the thrombomodulin Ala455Val variant allele emerges as a significant risk factor for coronary heart disease.