Kaj Metsärinne

Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial

BACKGROUND Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage. METHODS The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101. FINDINGS 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13.4%]) and ramipril (1150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01-1.18, p=0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89-1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01-1.51, p=0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2] mL/min/1.73 m(2)vs -4.12 [17.4], p<0.0001) or combination therapy (-6.11 [17.9], p<0.0001). The increase in urinary albumin excretion was less with telmisartan (p=0.004) or with combination therapy (p=0.001) than with ramipril. INTERPRETATION In people at high vascular risk, telmisartans effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease

BACKGROUND We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS In this double‐blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban‐plus‐aspirin group after a mean follow‐up of 23 months. RESULTS The primary outcome occurred in fewer patients in the rivaroxaban‐plus‐aspirin group than in the aspirin‐alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=‐4.126), but major bleeding events occurred in more patients in the rivaroxaban‐plus‐aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban‐plus‐aspirin group as compared with 378 (4.1%) in the aspirin‐alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban‐alone group than in the aspirin‐alone group, but major bleeding events occurred in more patients in the rivaroxaban‐alone group. CONCLUSIONS Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424.)

Asbestos exposure as a risk factor for retroperitoneal fibrosis

BACKGROUND Retroperitoneal fibrosis (RPF) is an uncommon disease with unknown causation in most cases. The pathognomonic finding is a fibrous mass covering the abdominal aorta and the ureters. Our aim was to clarify the possible role of asbestos exposure in the development of RPF. The hypothesis was based on the ability of asbestos to cause fibrosis in pulmonary and pleural tissue. METHODS We undertook a case-control study of 43 patients with the disease (86% of eligible cases) treated in three university hospital districts of Finland in 1990-2001. For every patient, five population-based controls were selected, matched by age, sex, and central hospital district. We assessed asbestos exposure and medical history using a postal questionnaire and a personal interview. Of the 215 eligible controls, 179 (83%) participated in the study. FINDINGS The age-standardised incidence of RPF was 0.10 (95% CI 0.07-0.14) per 100?000 person-years. The disease was strongly associated with asbestos exposure. The odds ratio (OR) was 5.54 (1.64-18.65) for less than 10 fibre-years of asbestos exposure and 8.84 (2.03-38.50) for 10 or more fibre-years, the attributable fraction being 82% and 89%, respectively. Other risk factors were previous use of ergot derivates (OR 9.92 [1.63-60.26]), abdominal aortic aneurysm (OR 6.73 [0.81-56.08]), and smoking for more than 20 pack-years (OR 4.73 [1.28-17.41]). INTERPRETATION Our results show that occupational asbestos exposure is an important causal factor for RPF. For patients with work-related asbestos exposure, RPF should be considered an occupational disease.

Neurophysiologic parameters and symptoms in chronic renal failure

We studied: (1) the sensitivity of various neurophysiologic parameters in the diagnosis of uremic polyneuropathy, (2) the relationship between subjective symptoms and neurophysiologic parameters, and (3) the effect of a single hemodialysis on the neurophysiologic parameters in 21 patients undergoing hemodialysis. The following parameters were studied: sensory and motor nerve conduction, including F‐wave parameters; vibration detection thresholds; and thermal thresholds. The clinical findings and subjective symptoms were studied using a standardized questionnaire. The most sensitive parameters in the diagnosis of uremic neuropathy were F‐wave parameters from lower limbs, vibration detection thresholds from the feet, and the sural nerve sensory action potential amplitude. The nerves from the upper extremities on the side of the fistula should not be used in the diagnosis of uremic polyneuropathy due to numerous mild local nerve lesions. The positive neuropathic symptoms correlated with quantitative vibratory detection thresholds and sensory nerve conduction studies, especially the amplitude of the sensory nerve action potential in the sural nerve. We found no significant change in any of the neurophysiologic parameters following a single hemodialysis session.

Long-term outcome of infective endocarditis: a study on patients surviving over one year after the initial episode treated in a Finnish teaching hospital during 25 years.

BackgroundOnly a few previous studies have focused on the long-term prognosis of the patients with infective endocarditis (IE). Our purpose was to delineate factors potentially associated with the long-term outcome of IE, recurrences of IE and requirement for late valve surgery.MethodsA total of 326 episodes of IE in 303 patients were treated during 1980–2004 in the Turku University Hospital. We evaluated the long-term outcome and requirement for late valve surgery for 243 of these episodes in 226 patients who survived longer than 1 year after the initial admission. Factors associated with recurrences were analysed both for the 1-year survivors and for all 303 patients.ResultsThe mean (SD) follow-up time for the 1-year survivors was 11.5 (7.3) years (range 25 days to 25.5 years). The overall survival was 95%, 82%, 66%, 51% and 45% at 2, 5, 10, 15 and 20 years. In age and sex adjusted multivariate analyses, significant predictors for long-term overall mortality were heart failure within 3 months of admission (HR 1.97, 95% CI 1.27 to 3.06; p = 0.003) and collagen disease (HR 2.54, 95% CI 1.25 to 5.19; p = 0.010) or alcohol abuse (HR 2.39, 95% CI 1.30 to 4.40; p = 0.005) as underlying conditions, while early surgery was significantly associated with lower overall mortality rates (HR 0.31, 95% CI 0.17 to 0.58; p < 0.001). Heart failure was also significantly associated with the long-term cardiac mortality (p = 0.032). Of all 303 patients, 20 had more than 1 disease episode. Chronic dialysis (p = 0.002), intravenous drug use (p = 0.002) and diabetes (p = 0.015) were significant risk factors for recurrent episodes of IE, but when analysed separately for the 1-year survivors, only chronic dialysis remained significant (p = 0.017). Recurrences and late valve surgery did not confer a poor prognosis.ConclusionHeart failure during the index episode of IE was the complication, which significantly predicted a poor long-term outcome. Patients who underwent surgery during the initial hospitalisation for IE faired significantly better than those who did not.

Intravenous administration of low molecular weight and unfractionated heparin elicits a rapid increase in serum pregnancy-associated plasma protein A.

BACKGROUND Pregnancy-associated plasma protein A (PAPP-A) has been suggested as a useful diagnostic and prognostic marker in acute coronary syndromes. Because low molecular weight heparin (LMWH) and unfractionated heparin (UFH) are commonly used in these cases, we analyzed the effects of intravenous administration of these heparins on serum PAPP-A concentrations. METHODS Serum concentrations of total and free PAPP-A were analyzed in 14 patients on chronic hemodialysis and in 10 coronary angiography patients. Ten of the dialysis patients received standard LMWH anticoagulation at the start of dialysis, and 4 were treated with a heparin-free method. Two of the patients on heparin-free hemodialysis received a reduced LMWH bolus 2 h after the start of dialysis. All angiography patients received UFH at the start of the procedure, and 1 patient received 2 extra boluses of UFH. Serum PAPP-A concentrations were analyzed before and during the dialysis session and during the coronary angiography examination. RESULTS A rapid increase in total PAPP-A (median, 25-fold) was seen in all patients within 5 min of administration for both LMWH and UFH boluses. This response was due to an increase in free PAPP-A in the serum. PAPP-A did not increase significantly in the patients who underwent heparin-free hemodialysis. Repeated heparin boluses induced a new PAPP-A release. In vitro addition of heparins to samples of whole blood did not increase PAPP-A concentrations. CONCLUSIONS Intravenous administration of heparin induces an intense and rapid increase in free PAPP-A in the serum. We recommend that this effect be considered when PAPP-A is assessed as a biomarker in acute coronary syndromes.

Rationale, Design and Baseline Characteristics of Participants in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) Trial

BACKGROUND Long-term aspirin prevents vascular events but is only modestly effective. Rivaroxaban alone or in combination with aspirin might be more effective than aspirin alone for vascular prevention in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). Rivaroxaban as well as aspirin increase upper gastrointestinal (GI) bleeding and this might be prevented by proton pump inhibitor therapy. METHODS Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) is a double-blind superiority trial comparing rivaroxaban 2.5 mg twice daily combined with aspirin 100 mg once daily or rivaroxaban 5 mg twice daily vs aspirin 100 mg once daily for prevention of myocardial infarction, stroke, or cardiovascular death in patients with stable CAD or PAD. Patients not taking a proton pump inhibitor were also randomized, using a partial factorial design, to pantoprazole 40 mg once daily or placebo. The trial was designed to have at least 90% power to detect a 20% reduction in each of the rivaroxaban treatment arms compared with aspirin and to detect a 50% reduction in upper GI complications with pantoprazole compared with placebo. RESULTS Between February 2013 and May 2016, we recruited 27,395 participants from 602 centres in 33 countries; 17,598 participants were included in the pantoprazole vs placebo comparison. At baseline, the mean age was 68.2 years, 22.0% were female, 90.6% had CAD, and 27.3% had PAD. CONCLUSIONS COMPASS will provide information on the efficacy and safety of rivaroxaban, alone or in combination with aspirin, in the long-term management of patients with stable CAD or PAD, and on the efficacy and safety of pantoprazole in preventing upper GI complications in patients receiving antithrombotic therapy.

Increased basal myocardial perfusion in patients with chronic kidney disease without symptomatic coronary artery disease

BACKGROUND Even minor renal dysfunction is a powerful cardiovascular risk factor. The abnormalities in coronary and peripheral artery function in different stages of chronic kidney disease (CKD) remain poorly understood. Our aim was to test by a positron emission tomography (PET)-based method whether microvascular dysfunction, an early marker of coronary dysfunction, exists already in early stages of CKD. METHODS Myocardial blood flow was measured at baseline and during dipyridamole-induced hyperaemia by PET. Peripheral artery endothelial function was examined by measuring flow-mediated dilatation (FMD) of the brachial artery at rest and during reactive hyperaemia. Twenty-two patients with moderate to severe kidney failure and 10 healthy controls were investigated. Diabetic patients were excluded. Baseline characteristics were similar between the groups with the exception of antihypertensive medication in all CKD patients. RESULTS The basal myocardial perfusion was statistically significantly higher in CKD patients than observed values in similarly aged controls. There was a statistically significant negative correlation between the baseline myocardial perfusion and the estimated glomerular filtration rate. Coronary flow reserve was comparable to healthy controls in all patients. FMD was significantly reduced in all patients with CKD regardless of the stage of kidney failure. CONCLUSIONS Coronary flow reserve was normal although baseline myocardial blood flow was increased in all CKD patients as compared to healthy controls. Peripheral endothelial dysfunction was detected in all patients. Our findings suggest that coronary perfusion and peripheral vascular function are disturbed by different mechanisms in patients with CKD.

High prevalence of chronic kidney disease in Finnish patients with type 2 diabetes treated in primary care

OBJECTIVE To examine the prevalence of chronic kidney disease (CKD) and related cardiovascular morbidity in a cross-sectional population in patients with type 2 diabetes (T2D) treated in a primary care setting in Finland. RESEARCH DESIGN AND METHODS Data were collected and recorded from 42 primary care centres, which recruited 629 patients diagnosed with type 2 diabetes (T2D) to this non-interventional study. Data including patient characteristics, kidney function and albuminuria, blood pressure, HbA1c, lipid and lipoprotein levels, and diabetes duration as well as current medication was collected in each patient. RESULTS In the final study population of 625 patients, the mean age was 67 years (range 29-92 years), BMI 32.8 kg/m(2) (95% CI 32-33), blood pressure 142/80 mmHg (140-143/80-81) and HbA1c 7.1% (7.0-7.2) (53.8 mmol/mol, 53-55) and the median duration of diabetes was 9.2 years ranging from newly diagnosed to 43 years. History of dyslipidemia had in 73.3% of patients, 27.8% had cardiovascular disease and 82.7% had hypertension. The primary endpoint, prevalence of CKD of any grade (1-5) or albuminuria, was 68.6%. Regarding declined renal function, 16.2% of patients had an estimated glomerular filtration rate (eGFR) <60 ml/min/1.72 m(2), classifying as CKD 3-5. Only one patient was within CKD5. Regarding renal damage, albuminuria was present in 24.3% of patients, with microalbuminuria in 17.1% and macroalbuminuria in 7.2%, respectively. Combining the patients with CKD 3-5 and/or the presence of albuminuria, 34.7% seemed to suffer from significant CKD. The proportion of patients with albuminuria increased with a decrease in glomerular filtration rate. Historically, diabetic nephropathy had been diagnosed in 24.3% of the patients. CONCLUSIONS Nearly 70% of patients with T2D treated in primary care in Finland have some sign of CKD and nearly half of all T2D patients have a significant CKD. However, only half of the latter had it diagnosed and documented in their patient charts, thus highlighting the importance of performing routine screening of nephropathy by measuring both albuminuria and eGFR in patients with T2D. Prevention of this complication with active therapy for risk factors, such as hypertension and dyslipidemia is warranted.

Amino-acid-based peritoneal dialysis solution improves amino-acid transport into skeletal muscle

Abnormalities of amino-acid (AA) and protein metabolism are known to occur in chronic kidney disease (CKD). Protein malnutrition may contribute to impaired prognosis of dialysis patients. A crucial step in protein metabolism is AA transport into the cells. We compared the effects of an AA-containing peritoneal dialysis (PD) solution to glucose-based solutions on skeletal muscle AA uptake. Thirteen nondiabetic PD patients were studied twice in a random order and in a crossover manner both in the fasting state and during euglycemic insulin stimulation using [(11)C]methylaminoisobutyrate ([(11)C]MeAIB) and positron emission tomography (PET). Before both PET study days, patients had been using either glucose-based PD solutions only or one daily bag of AA solution in addition to glucose-based PD solutions for at least 6 weeks. Skeletal muscle AA uptake was calculated with graphical analysis. AA-containing PD solution increased plasma AA concentrations from 2.18+/-0.34 to 3.08+/-0.55 mmol l(-1) in the fasting state (P=0.0002) and from 1.88+/-0.15 to 2.42+/-0.30 mmol l(-1) during insulin stimulation (P<0.0001). As compared to PD treatment using glucose-based solutions only, skeletal muscle AA uptake was significantly higher during treatment containing AA solution both in the fasting state (15.2+/-5.8 vs 20.0+/-5.6 micromol kg(-1) min(-1), respectively, P=0.0057) and during insulin stimulation (16.8+/-4.5 vs 21.1+/-4.9 micromol kg(-1) min(-1), respectively, P=0.0046). In conclusion, PD treatment with an AA-containing PD solution is associated with a significant increase in skeletal muscle AA uptake both in the fasting state and during insulin stimulation.