Inclusion of Stroke as an Outcome and Risk Equivalent in Risk Scores for Primary and Secondary Prevention of Vascular Disease

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Heart rate is a prognostic risk factor for myocardial infarction: A post hoc analysis in the PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack) study population

<scp>LEADER</scp> and the new ‘cardiovascular’ glucose‐lowering agents

Background and Aims Coronary artery disease is prevalent in patients with CKD but how often a myocardial infarction (MI) occurs in patients on maintenance haemodialysis, and the prognostic importance of these MIs, is uncertain. The PIVOTAL trial investigated the effects of proactive high-dose versus reactive low-dose intravenous (IV) iron in incident haemodialysis patients. We now report the rates of MI, sub-types of MI, and the prognostic importance of these MIs, as well as the effect of high versus low dose iron on this event. Method This was a pre-specified secondary analysis of 2141 patients enrolled in the PIVOTAL trial. All potential endpoints in the trial, including MIs were adjudicated by a blinded Endpoint Adjudication Committee. The outcomes of time-to-first MI (type 1 or type 2 MI, STEMI or NSTEMI) and the composite outcome of MI and death due to MI were reported. In addition to time-to-first MI, we also analysed recurrent events, to account for the cumulative burden of events over time, as well as case-fatality related to MI. The time-to-event analyses of the primary, secondary and post hoc outcomes were performed in the intention-to-treat population using Cox proportional hazards regression, with treatment group as the only explanatory variable. The Kaplan–Meier method was used to estimate event rates. Recurrent events were analysed using the proportional-means model of Lin et al. and described in the form of mean frequency functions. Results 8.4% of patients experienced a MI over a median of 2.1 years follow-up. Rates of type 1 MIs (3.2/100 patient years) were 2.5 times higher than type 2 MIs (1.3/100 patient years). NSTEMIs (3.3/100 patient years) were 6.6 times more common than STEMIs (0.5/100 patient years). Mortality was high after non-fatal MI (30-day and 1-year mortality were 11.3% and 39.8%, respectively). In time-to-first event analyses, proactive high-dose IV iron reduced the rate of non-fatal MI (HR 0.69, 95% CI 0.51-0.93; p=0.01) and the composite endpoint of non-fatal and fatal MI (HR 0.69, 95% CI 0.52-0.93, p=0.015) (Figure) when compared to low dose reactive IV iron. The benefits of a proactive high-dose IV iron strategy were seen in type 1 MIs but not type 2 MIs. Conclusion Most MIs in patients on HD were type 1 and NTEMIs. Patients randomised to the high-dose group of PIVOTAL had a substantial reduction in fatal and non-fatal MI compared to those in the low-dose group.

Based upon community myocardial infarction (MI) records in five Swedish cities, geographical variation and time trends in the attack rate of fatal and non-fatal MI have been evaluated. During the study period 1975-1982, a total of 7699 events were registered among men and 1823 events among women. The mean annual mortality was highest in the north, and a declining gradient in mortality was observed from the northern to the southern part of the country. The out-of-hospital death rate was highest in the north, while no difference in in-hospital mortality was observed. However, the geographical variation in the morbidity of MI was less consistent. Changes over time generally followed the same pattern in all cities. The attack rate of fatal and non-fatal MI tended to decline among women and men aged 60-64 years. The pattern was less consistent among younger men. Among women aged 50-59 years the mortality remained unchanged, but the attack rate of non-fatal MI increased in all cities. This increase was not explained by inclusion of less severe infarctions. A considerable proportion, about 85%, were recorded as primary events, emphasizing the possible role of primary prevention in obtaining a decrease in the incidence of the disease. The results of this study support previous findings of an important regional difference in the mortality of MI in Sweden. However, the magnitude of the regional variation in the incidence of coronary heart disease might be overestimated if only the mortality pattern is studied.

BackgroundThere is a lack of data on the relationship between glycemic control and cardiovascular end points in hemodialysis patients with diabetes mellitus.Methods and ResultsWe included adult Medicare‐insured patients with diabetes mellitus who initiated in‐center hemodialysis treatment from 2006 to 2008 and survived for >90 days. Quarterly mean time‐averaged glycated hemoglobin (HbA1c) values were categorized into <48 mmol/mol (<6.5%) (reference), 48 to <58 mmol/mol (6.5% to <7.5%), 58 to <69 mmol/mol (7.5% to <8.5%), and ≥69 mmol/mol (≥8.5%). Medicare claims were used to identify outcomes of cardiovascular mortality, nonfatal myocardial infarction (MI), fatal or nonfatal MI, stroke, and peripheral arterial disease. We used Cox models as a function of time‐varying exposure to estimate multivariable adjusted hazard ratios and 95%CI for the associations between HbA1c and time to study outcomes in a cohort of 16 387 eligible patients. Patients with HbA1c 58 to <69 mmol/mol (7.5% to <8.5%) and ≥69 mmol/mol (≥8.5%) had 16% (CI, 2%, 32%) and 18% (CI, 1%, 37%) higher rates of cardiovascular mortality (P‐trend=0.01) and 16% (CI, 1%, 33%) and 15% (CI, 1%, 32%) higher rates of nonfatal MI (P‐trend=0.05), respectively, compared with those in the reference group. Patients with HbA1c ≥69 mmol/mol (≥8.5%) had a 20% (CI, 2%, 41%) higher rate of fatal or nonfatal MI (P‐trend=0.02), compared with those in the reference group. HbA1c was not associated with stroke, peripheral arterial disease, or all‐cause mortality.ConclusionsHigher HbA1c levels were significantly associated with higher rates of cardiovascular mortality and MI but not with stroke, peripheral arterial disease, or all‐cause mortality in this large cohort of hemodialysis patients with diabetes mellitus.

Hypertension and cardiovascular disease risk in women.

IntroductionMost current clinical risk prediction scores for cardiovascular disease prevention use a composite outcome. Risk prediction scores for specific cardiovascular events could identify people who are at higher risk for some events than others informing personalized care and trial recruitment. We sought to predict risk for multiple different events, describe how those risks differ, and examine if these differences could improve treatment priorities.MethodsWe used participant-level data from five cohort studies. We included participants between 40 and 79 years old who had no history of myocardial infarction (MI), stroke, or heart failure (HF). We made separate models to predict 10-year rates of first atherosclerotic cardiovascular disease (ASCVD), first fatal or nonfatal MI, first fatal or nonfatal stroke, new-onset HF, fatal ASCVD, fatal MI, fatal stroke, and all-cause mortality using established ASCVD risk factors. To limit overfitting, we used elastic net regularization with alpha = 0.75. We assessed the models for calibration, discrimination, and for correlations between predicted risks for different events. We also estimated the potential impact of varying treatment based on patients who are high risk for some ASCVD events, but not others.ResultsOur study included 24,505 people; 55.6% were women, and 20.7% were non-Hispanic Black. Our models had C-statistics between 0.75 for MI and 0.85 for HF, good calibration, and minimal overfitting. The models were least similar for fatal stroke and all MI (0.58). In 1,840 participants whose risk of MI but not stroke or all-cause mortality was in the top quartile, we estimate one blood pressure-lowering medication would have a 2.4% chance of preventing any ASCVD event per 10 years. A moderate-strength statin would have a 2.1% chance. In 1,039 participants who had top quartile risk of stroke but not MI or mortality, a blood pressure-lowering medication would have a 2.5% chance of preventing an event, but a moderate-strength statin, 1.6%.ConclusionWe developed risk scores for eight key clinical events and found that cardiovascular risk varies somewhat for different clinical events. Future work could determine if tailoring decisions by risk of separate events can improve care.

ATP III recognizes that detection of cholesterol disorders and other coronary heart disease (CHD) risk factors occurs primarily through clinical case finding. Risk factors can be detected and evaluated as part of a person's work-up for any medical problem. Alternatively, public screening programs can identify risk factors, provided that affected individuals are appropriately referred for physician attention. The identification of cholesterol disorders in the setting of a medical examination has the advantage that other cardiovascular risk factors—including prior CHD, PVD, stroke, age, gender, family history, cigarette smoking, high blood pressure, diabetes mellitus, obesity, physical inactivity—co-morbidities, and other factors can be assessed and considered prior to treatment. At the time of physician evaluation, the person's overall risk status is assessed. Thus, detection and evaluation of cholesterol and lipoprotein problems should proceed in parallel with risk assessment for CHD. The approach to both is described below. The guiding principle of ATP III is that the intensity of LDL-lowering therapy should be adjusted to the individual's absolute risk for CHD. In applying this principle, ATP III maintains that both short-term (≤10-year) and long-term (> 10-year) risk must be taken into consideration. Thus, treatment guidelines are designed to incorporate risk reduction for both short-term and long-term risk (composite risk). ATP III identifies three categories of risk for CHD that modify goals and modalities of LDL-lowering therapy: established CHD and CHD risk equivalents, multiple (2+) risk factors, and 0-1 risk factor (Table III.1-1). View this table: Table III.1-1. Categories of Risk for Coronary Heart Disease (CHD) ### a. Identification of persons with CHD and CHD risk equivalents Coronary heart disease . Persons with CHD are at very high risk for future CHD events (10-year risk >20 percent). Several clinical patterns constitute a diagnosis of CHD; these include history of acute myocardial infarction, evidence of silent myocardial infarction or myocardial ischemia, history of unstable angina and stable angina pectoris, and history …

Background Cardiovascular disease (CVD) is the leading cause of death among SLE patients, with significantly elevated risks of myocardial infarction (MI) and stroke among SLE patients compared to age-matched controls. The objective of our study was to examine the rates of non-fatal MI, stroke, and the combined endpoint of non-fatal MI or stroke, overall and by race/ethnicity, among SLE patients enrolled in Medicaid. Materials and methods Within Medicaid Analytic eXtract (MAX), containing billing claims from 2000–10 for Medicaid patients from the 29 most populated US states, we identified patients aged 18–65 with prevalent SLE (≥ 3 ICD-9 codes 710.0, ≥30 days apart) with >12 months of continuous enrollment prior to 3 rd code (index date). Baseline data from 12 months prior to index date included age, sex, race/ethnicity, zip code, year, SLE-related and other comorbidities, including CVD risk factors (based on ICD-9 and DRG codes). Those missing race/ethnicity were excluded. Subjects were followed from index date to first MI or stroke event, death, Medicaid disenrollment, or end of follow-up. MI, stroke, and combined outcome per 1000 person-years with 95% CIs were calculated overall and by race/ethnicity. Subdistribution proportional hazards regression models, accounting for the competing risk of death, were used to calculate multivariable-adjusted hazard ratios (HRsd) for MI, stroke, and combined outcome. Results Among 43,448 cases with prevalent SLE, 93.6% were female. Racial/ethnic breakdown was: 41% Black, 39% White, 15% Hispanic, 3% Asian, 1% Native American. Mean follow-up was 3.48 ± 2.86 years for all SLE patients. Overall crude rates were highest among Native Americans for MI, Blacks for stroke, and Native Americans for MI or stroke. Hispanics had the lowest overall crude rates for MI, stroke, and the combined outcome. After multivariable adjustment and accounting for the competing risk of death, Hispanics had lower MI risk (HRsd] 0.59 [95% CI: 0.42–0.84]) and Blacks had elevated risk of stroke (HRsd 1.36 [95% CI: 1.15–1.60]) as compared with Whites. For the outcome of MI or stroke, Blacks had an elevated risk (HRsd 1.22 [95% CI: 1.07–1.38], whereas Hispanics had a lower risk (HR 0.82 [95% CI: 0.67 to 0.99] compared to Whites. Conclusions Marked race/ethnicity-specific variation exists in MI and stroke risks among Medicaid patients with SLE. Elevated CVD risks among Blacks and lower risks among Hispanics may account for some of the excess all-cause mortality observed among Black patients and lower overall mortality among Hispanics with SLE as previously described.

Review of cholesterol-lowering therapy: Coronary angiographic and events trials

A health survey of middle-aged men was carried out in 1970-73 in the municipality of Uppsala. Subjects with hypertension, hyperlipidaemia, reduced glucose tolerance, and smokers were invited to join various therapy groups. By 1980 this multifactorial intervention programme had thus been running for 10 years. This report describes the results of a follow-up undertaken to evaluate the efficacy of the programme. The annual rate of fatal myocardial infarction (MI) was lower among the participants (n = 2322) in the health examination as well as among participants and non-participants (n = 446) combined than among the male Swedish population of the same age (162 and 187 compared with 296 per 100 000 men, respectively). The annual rate of non-fatal MI among participants and non-participants combined was 295 per 100 000 men, which is lower than in other Swedish cities. In the hypertensive group (n = 126), six men had fatal and seven non-fatal MI. These 13 men had higher blood pressures (BPs) from the start than the other hypertensives. In addition, their BP reduction was smaller than in a control group randomly selected among the hypertensive subjects. In the hyperlipidaemic treatment group (n = 363) there were eight fatal and 10 non-fatal MIs. Nine of these events occurred in individuals who had dropped out from therapy. It is suggested that the low total mortality and the low rates of fatal and non-fatal MI in this middle-aged male population may be related to the multifactorial intervention programme, as the incidences were also low among the treated high-risk groups.

The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established. We enrolled in our study 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both to assess the cardiovascular consequences of weight management with and without sibutramine in subjects at high risk for cardiovascular events. All the subjects received sibutramine in addition to participating in a weight-management program during a 6-week, single-blind, lead-in period, after which 9804 subjects underwent random assignment in a double-blind fashion to sibutramine (4906 subjects) or placebo (4898 subjects). The primary end point was the time from randomization to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death). The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P=0.03). The rates of cardiovascular death and death from any cause were not increased. Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.)

Racial and ethnic differences in incident myocardial infarction in end-stage renal disease patients: The USRDS

Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial