Ulf de Faire

Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol

BACKGROUND Blood pressure reduction achieved with beta-blockers and diuretics is the best recorded intervention to date for prevention of cardiovascular morbidity and death in patients with hypertension. Left ventricular hypertrophy (LVH) is a strong independent indicator of risk of cardiovascular morbidity and death. We aimed to establish whether selective blocking of angiotensin II improves LVH beyond reducing blood pressure and, consequently, reduces cardiovascular morbidity and death. METHODS We did a double-masked, randomised, parallel-group trial in 9193 participants aged 55-80 years with essential hypertension (sitting blood pressure 160-200/95-115 mm Hg) and LVH ascertained by electrocardiography (ECG). We assigned participants once daily losartan-based or atenolol-based antihypertensive treatment for at least 4 years and until 1040 patients had a primary cardiovascular event (death, myocardial infarction, or stroke). We used Cox regression analysis to compare regimens. FINDINGS Blood pressure fell by 30.2/16.6 (SD 18.5/10.1) and 29.1/16.8 mm Hg (19.2/10.1) in the losartan and atenolol groups, respectively. The primary composite endpoint occurred in 508 losartan (23.8 per 1000 patient-years) and 588 atenolol patients (27.9 per 1000 patient-years; relative risk 0.87, 95% CI 0.77-0.98, p=0.021). 204 losartan and 234 atenolol patients died from cardiovascular disease (0.89, 0.73-1.07, p=0.206); 232 and 309, respectively, had fatal or non-fatal stroke (0.75, 0.63-0.89, p=0.001); and myocardial infarction (non-fatal and fatal) occurred in 198 and 188, respectively (1.07, 0.88-1.31, p=0.491). New-onset diabetes was less frequent with losartan. Interpretation Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated. Losartan seems to confer benefits beyond reduction in blood pressure.

Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol

BACKGROUND The most suitable antihypertensive drug to reduce the risk of cardiovascular disease in patients with hypertension and diabetes is unclear. In prespecified analyses, we compared the effects of losartan and atenolol on cardiovascular morbidity and mortality in diabetic patients. METHODS As part of the LIFE study, in a double-masked, randomised, parallel-group trial, we assigned a group of 1195 patients with diabetes, hypertension, and signs of left-ventricular hypertrophy (LVH) on electrocardiograms losartan-based or atenolol-based treatment. Mean age of patients was 67 years (SD 7) and mean blood pressure 177/96 mm Hg (14/10) after placebo run-in. We followed up patients for at least 4 years (mean 4.7 years [1.1]). We used Cox regression analysis with baseline Framingham risk score and electrocardiogram-LVH as covariates to compare the effects of the drugs on the primary composite endpoint of cardiovascular morbidity and mortality (cardiovascular death, stroke, or myocardial infarction). FINDINGS Mean blood pressure fell to 146/79 mm Hg (17/11) in losartan patients and 148/79 mm Hg (19/11) in atenolol patients. The primary endpoint occurred in 103 patients assigned losartan (n=586) and 139 assigned atenolol (n=609); relative risk 0.76 (95% CI 0.58-.98), p=0.031. 38 and 61 patients in the losartan and atenolol groups, respectively, died from cardiovascular disease; 0.63 (0.42-0.95), p=0.028. Mortality from all causes was 63 and 104 in losartan and atenolol groups, respectively; 0.61 (0.45-0.84), p=0.002. INTERPRETATION Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension, diabetes, and LVH. Losartan seems to have benefits beyond blood pressure reduction.

Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study

BACKGROUND The efficacy of new antihypertensive drugs has been questioned. We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients. METHODS We did a prospective, randomised trial in 6614 patients aged 70-84 years with hypertension (blood pressure > or = 180 mm Hg systolic, > or = 105 mm Hg diastolic, or both). Patients were randomly assigned conventional antihypertensive drugs (atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg, or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily) or newer drugs (enalapril 10 mg or lisinopril 10 mg, or felodipine 2.5 mg or isradipine 2-5 mg daily). We assessed fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease. Analysis was by intention to treat. FINDINGS Blood pressure was decreased similarly in all treatment groups. The primary combined endpoint of fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group (19.8 events per 1000 patient-years) and in 438 of 4401 in the newer drugs group (19.8 per 1000; relative risk 0.99 [95% CI 0.84-1.16], p=0.89). The combined endpoint of fatal and non-fatal stroke, fatal and non-fatal myocardial infarction, and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs (0.96 [0.86-1.08], p=0.49). INTERPRETATION Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events. Decrease in blood pressure was of major importance for the prevention of cardiovascular events.

Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study

BACKGROUND Calcium antagonists are a first-line treatment for hypertension. The effectiveness of diltiazem, a non-dihydropyridine calcium antagonist, in reducing cardiovascular morbidity or mortality is unclear. We compared the effects of diltiazem with that of diuretics, beta-blockers, or both on cardiovascular morbidity and mortality in hypertensive patients. METHODS In a prospective, randomised, open, blinded endpoint study, we enrolled 10,881 patients, aged 50-74 years, at health centres in Norway and Sweden, who had diastolic blood pressure of 100 mm Hg or more. We randomly assigned patients diltiazem, or diuretics, beta-blockers, or both. The combined primary endpoint was fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death. Analysis was done by intention to treat. FINDINGS Systolic and diastolic blood pressure were lowered effectively in the diltiazem and diuretic and beta-blocker groups (reduction 20.3/18.7 vs 23.3/18.7 mm Hg; difference in systolic reduction p<0.001). A primary endpoint occurred in 403 patients in the diltiazem group and in 400 in the diuretic and beta-blocker group (16.6 vs 16.2 events per 1000 patient-years; relative risk 1.00 [95% CI 0.87-1.15], p=0.97). Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 in the diuretic and beta-blocker group (6.4 vs 7.9 events per 1000 patient-years; 0.80 [0.65-0.99], p=0.04) and fatal and non-fatal myocardial infarction in 183 and 157 patients (7.4 vs 6.3 events per 1000 patient-years; 1.16 [0.94-1.44], p=0.17). INTERPRETATION Diltiazem was as effective as treatment based on diuretics, beta-blockers, or both in preventing the combined primary endpoint of all stroke, myocardial infarction, and other cardiovascular death.

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

Summary Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

Relation between drug treatment and cancer in hypertensives in the Swedish Trial in Old Patients with Hypertension 2: a 5-year, prospective, randomised, controlled trial

BACKGROUND Is cancer related to hypertension and blood pressure? Do antihypertensive drugs promote cancer? Do antihypertensive drugs protect against cancer? We previously analysed the frequency of cardiovascular mortality and morbidity in elderly people who participated in the Swedish Trial in Old Patients with Hypertension 2 (STOP-Hypertension-2). We have also looked at the frequency of cancer in these patients. METHODS We randomly assigned 6614 elderly patients with hypertension (mean age 76 years, median time of follow-up 5.3 years) to one of three treatment strategies: conventional drugs (diuretics or b-blockers), calcium antagonists, or ACE inhibitors. We matched the patients to the Swedish Cancer Registry and compared our findings with expected values based on age, sex, and calendar-year-specific reference frequencies for the general Swedish population. We also compared the number of cancers between the three treatment groups. FINDINGS At baseline, 607 (9%) patients had previous malignant disease. Diagnoses were closely similar to the distribution of cancer types that might be seen in elderly patients. During follow-up, there were 625 new cases of cancer in 590 patients. The frequency of cancer did not differ significantly between the treatment strategies, including all cancers and those at individual sites. The standardised incidence ratios (SIRs) for all cancers were also close to unity: 0.92 (95% CI 0.80-1.06) for conventional drugs, 0.96 (0.83-1.10) for calcium antagonists, and 0.99 (0.86-1.13) for ACE inhibitors. INTERPRETATIONS No difference in cancer risk was seen between patients randomly assigned to conventional drugs, calcium antagonists, or ACE inhibitors. Thus, the general message to the practising physician is that more attention should be given to getting the blood pressure down than to the risk of cancer.

Lowering of blood pressure and predictors of response in patients with left ventricular hypertrophy : The LIFE study

The Losartan Intervention For Endpoint (LIFE) reduction in hypertension study is a double-blind, prospective, parallel-group study comparing the effects of losartan with those of atenolol on the reduction of cardiovascular complications in patients (n = 9,194) with essential hypertension and with electrocardiographically (ECG) documented left ventricular hypertrophy (LVH). Baseline blood pressure was 174.4/97.8 mm Hg (mean), age 66.9 years, body mass index 28.0 kg/m2; 54.1% were women and 12.5% had diabetes mellitus. This population will be treated until at least 1,040 have a primary endpoint. After five scheduled visits and 12 months of follow-up, blood pressure decreased by 23.9/12.8 mm Hg to 150.5/85.1 mm Hg (target < 140/90 mm Hg). The mandatory titration level of < or = 160/95 mm Hg was reached by 72.1% of the patients. At the 12-month visit, 22.7% of all patients were taking blinded study drug alone, 44.3% were taking blinded drug plus hydrochlorothiazide (HCTZ), and 17.7% were taking blinded drugs plus HCTZ and additional drugs. Controlling for all other variables, patients in the US received more medication and had 2.4 times the odds of achieving blood pressure control than patients in the rest of the study (P < .001). Previously untreated patients (n = 2,530) had a larger initial decrease in blood pressure compared with those previously treated. Diabetics (n = 1,148) needed more medication than nondiabetics to gain blood pressure control. Only 13.9% of the patients had discontinued blinded study drug and 1.4% missed the revisit at 12 months. These data demonstrate both the successful lowering of blood pressure during 12 months of follow-up in a large cohort of patients with hypertension and LVH on ECG, but also emphasize the need for two or more drugs to control high blood pressure in most of these patients. Being previously treated and having diabetes were associated with less blood pressure response, whereas living in the US indicated better blood pressure control. It has been possible to keep most of these patients with complicated hypertension taking blinded study drug for 12 months.

Circulating PCSK9 Predicts Future Risk of Cardiovascular Events Independently of Established Risk Factors

Background —The secreted protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for lowering of plasma low-density lipoprotein (LDL) cholesterol and prevention of cardiovascular disease (CVD). The relationship between circulating PCSK9 and incident CVD in the general population is unknown. We investigated whether serum PCSK9 concentration is associated with incident CVD in a prospective cohort study of 4,232 men and women aged 60 at the time of recruitment. Methods and Results —Incident CVD was recorded by matching to national registries. After 15 years of follow-up, a total number of 491 incident events (fatal and non-fatal myocardial infarctions, unstable angina, deaths from coronary heart disease, fatal and non-fatal ischemic strokes) were recorded. Cox Proportional Hazards model was used to calculate Hazard ratios (HR) with 95% confidence intervals (CI). Baseline serum PCSK9 concentration predicted incident CVD; concentration in quartile 4, as compared to quartile 1, was associated with a HR of 1.69 (95% CI 1.30-2.19) after adjustment for sex. Further adjustment for LDL cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), triglycerides, hypertension, diabetes, smoking, overweight, obesity, physical inactivity and statin use resulted in a decrease of the HR: 1.48 (95% CI 1.12-1.95). Conclusions —Serum PCSK9 concentration is associated with future risk of CVD even after adjustments for established CVD risk factors. Further studies are needed to confirm this observation.Background— The secreted protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for lowering plasma low-density lipoprotein cholesterol and preventing cardiovascular disease (CVD). The relationship between circulating PCSK9 and incident CVD in the general population is unknown. We investigated whether serum PCSK9 concentration is associated with incident CVD in a prospective cohort study of 4232 men and women 60 years of age at the time of recruitment. Methods and Results— Incident CVD was recorded by matching to national registries. After 15 years of follow-up, a total of 491 incident events (fatal and nonfatal myocardial infarctions, unstable angina, deaths from coronary heart disease, fatal and nonfatal ischemic strokes) were recorded. Cox proportional hazards model was used to calculate hazard ratios with 95% confidence intervals. Baseline serum PCSK9 concentration predicted incident CVD; concentration in quartile 4 compared with quartile 1 was associated with a hazard ratio of 1.69 (95% confidence interval, 1.30–2.19) after adjustment for sex. Further adjustment for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), triglycerides, hypertension, diabetes mellitus, smoking, overweight, obesity, physical inactivity, and statin use resulted in a decrease in the hazard ratio to 1.48 (95% confidence interval, 1.12–1.95). Conclusions— Serum PCSK9 concentration is associated with future risk of CVD even after adjustments for established CVD risk factors. Further studies are needed to confirm this observation.

Genetic Epidemiology of Spontaneous Subarachnoid Hemorrhage Nordic Twin Study

Background and Purpose— It would be essential to clinicians, familial aneurysm study groups, and aneurysm families to understand the genetic basis of subarachnoid hemorrhage (SAH), but there are no large population-based heritability estimates assessing the relative contribution of genetic and environmental factors to SAH. Methods— We constructed the largest twin cohort to date, the population-based Nordic Twin Cohort, which comprised 79 644 complete twin pairs of Danish, Finnish, and Swedish origin. The Nordic Twin Cohort was followed up for 6.01 million person-years using nationwide cause-of-death and hospitalization registries. Results— One hundred eighty-eight fatal and 321 nonfatal SAH cases were recorded in the Nordic Twin Cohort. Thus, SAH incidence was 8.47 cases per 100 000 follow-up years. Data for pairwise analyses were available for a total of 504 SAH cases, of which 6 were concordant (5 monozygotic and 1 opposite sex) and 492 discordant twin pairs for SAH. The concordance for SAH in monozygotic twins was 3.1% compared with 0.27% in dizygotic twins, suggesting at most a modest role for genetic factors in the etiology of SAH. The population-based probability estimate for SAH in dizygotic siblings of a patient with SAH is 0.54%, and only 1 of 185 full siblings experience familial SAH. The corresponding risk of SAH in monozygotic twins is 5.9%. Model-fitting, which was based on the comparison of the few monozygotic and dizygotic pairs, suggested that the estimated heritability of SAH is 41%. Conclusions— SAH appears to be mainly of nongenetic origin, and familial SAHs can mostly be attributed to environmental risk factors.

The effects of losartan compared to atenolol on stroke in patients with isolated systolic hypertension and left ventricular hypertrophy. The LIFE study.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study reported that a losartan‐based antihypertensive regimen reduced cardiovascular morbidity and mortality (composite of cardiovascular death, stroke, and myocardial infarction) more than therapy based on atenolol in patients with left ventricular hypertrophy and isolated systolic hypertension (ISH). Patients aged 55–80 years with blood pressures 160–200/<90 mm Hg were followed for a mean of 4.7 years. Blood pressure was similarly reduced in the losartan (n=660) and atenolol (n=666) ISH groups. There were 88 (6.6%) patients who experienced a stroke, 18 of which were fatal. Of patients experiencing strokes, 72.7% had an ischemic stroke. ISH patients in LIFE compared to the non‐ISH group had a higher incidence of any stroke and embolic stroke, and similar incidences of fatal, atherosclerotic, and hemorrhagiclother strokes. The incidence of any stroke (40% risk reduction [RR], p=0.02), fatal stroke (70% RR, p=0.035), and atherothrombotic stroke (45% RR, p=0.022) was significantly lower in losartan‐treated compared to the atenolol‐treated patients. The 36% RR for embolic strokes in the losartan group was not statistically significantly (p=0.33) different from the atenolol group. These data suggest that losartan‐based treatment is more effective than an atenolol‐based treatment for patients with ISH and a high risk for stroke.