Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes

OBJECTIVE: To assess whether ACE inhibitors are superior to alternative agents for the prevention of cardiovascular events in patients with hypertension and type 2 diabetes. RESEARCH DESIGN AND METHODS: This study is a review and meta-analysis of randomized controlled trials that included patients with type 2 diabetes and hypertension who were randomized to an ACE inhibitor or an alternative drug, were followed for > or =2 years, and had adjudicated cardiovascular events. RESULTS: A total of 4 trials were eligible. The Appropriate Blood Pressure Control in Diabetes (ABCD) trial (n = 470) compared enalapril with nisoldipine, the Captopril Prevention Project (CAPPP) (n = 572) compared captopril with diuretics or beta-blockers, the Fosinopril Versus Amlodipine Cardiovascular Events Trial (FACET) (n = 380) compared fosinopril with amlodipine, and the U.K. Prospective Diabetes Study (UKPDS) (n = 758) compared captopril with atenolol. The cumulative results of the first 3 trials showed a significant benefit of ACE inhibitors compared with alternative treatments on the outcomes of acute myocardial infarction (63% reduction, P < 0.001), cardiovascular events (51% reduction, P < 0.001), and all-cause mortality (62% reduction, P = 0.010). These findings were not observed in the UKPDS. The ACE inhibitors did not appear to be superior to other agents for the outcome of stroke in any of the trials. None of the findings were explained by differences in blood pressure control. CONCLUSIONS: Compared with the alternative agents tested, ACE inhibitors may provide a special advantage in addition to blood pressure control. The question of whether atenolol is equivalent to captopril remains open. Conclusive evidence on the comparative effects of antihypertensive treatments will come from large prospective randomized trials.     

Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study

BACKGROUND: Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events. Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure. METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination, and all subsequent cardiovascular events were ascertained and classified. RESULTS: At baseline, 1961 men and 2941 women were at risk for an incident myocardial infarction or stroke. During follow-up that averaged 6.7 years, 572 subjects had a coronary event, 385 had a stroke, and 896 died. After adjustment for potential confounders, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were directly associated with the risk of incident myocardial infarction and stroke. Only SBP was associated with total mortality. Importantly, SBP was a better predictor of cardiovascular events than DBP or pulse pressure. In the adjusted model for myocardial infarction, a 1-SD change in SBP, DBP, and pulse pressure was associated with hazard ratios (95% confidence intervals) of 1.24 (1.15-1.35), 1.13 (1.04-1.22), and 1.21 (1.12-1.31), respectively; and adding pulse pressure or DBP to the model did not improve the fit. For stroke, the hazard ratios (95% confidence intervals) were 1.34 (1.21-1.47) with SBP, 1.29 (1.17-1.42) with DBP, and 1.21 (1.10-1.34) with pulse pressure. The association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relationship. In those with treated hypertension, the hazard ratios for the association of SBP with the risks for myocardial infarction and stroke were less pronounced than in those without treated hypertension. CONCLUSION: In this population-based study of older adults, although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events, SBP was the best single predictor of cardiovascular events.     

Total insulinlike growth factor 1 and insulinlike growth factor binding protein levels, functional status, and mortality in older adults

OBJECTIVES: To assess the association between total insulinlike growth factor (IGF)‐1, IGF binding protein‐1 (IGFBP‐1), and IGFBP‐3 levels and functioning and mortality in older adults. DESIGN: Cohort study. SETTING/PARTICIPANTS: One thousand one hundred twenty‐two individuals aged 65 and older without prior cardiovascular disease events participating in the Cardiovascular Health Study. MEASUREMENTS: Baseline fasting plasma levels of IGF‐1, IGFBP‐1, and IGFBP‐3 (defined as tertiles, T1‐T3) were examined in relationship to handgrip strength, time to walk 15 feet, development of new difficulties with activities of daily living (ADLs), and mortality. RESULTS: Higher IGFBP‐1 predicted worse handgrip strength (P‐trend_T1‐T3<.01) and slower walking speed (P‐trend_T1‐T3=.03), lower IGF‐1 had a borderline significant association with worse handgrip strength (P‐trend_T1‐T3=.06), and better grip strength was observed in the middle IGFBP‐3 tertile than in the low or high tertiles (P=.03). Adjusted for age, sex, and race, high IGFBP‐1 predicted greater mortality (P‐trend_T1‐T3<.001, hazard ratio (HR)_T3vsT1=1.48, 95% confidence interval (CI)=1.15–1.90); this association was borderline significant after additional confounder adjustment (P‐trend_T1‐T3=.05, HR_T3vsT1=1.35, 95% CI=0.98–1.87). High IGFBP‐1 was associated with greater risk of incident ADL difficulties after adjustment for age, sex, race, and other confounders (P‐trend_T1‐T3=.04, HR_T3vsT1=1.40, CI=1.01–1.94). Neither IGF‐1 nor IGFBP‐3 level predicted mortality or incident ADL difficulties. CONCLUSION: In adults aged 65 and older, high IGFBP‐1 levels were associated with greater risk of mortality and poorer functional ability, whereas IGF‐1 and IGFBP‐3 had little association with these outcomes.     

Risk of myocardial infarction attributable to elevated levels of total cholesterol among hypertensives

BACKGROUND: Although cholesterol is an important risk factor for coronary heart disease (CHD) among hypertensives, the burden of CHD among hypertensives that may be due to elevated cholesterol has not been well documented. This study aimed to estimate the proportion of incident myocardial infarction (MI) among hypertensives that may be attributable to elevated total cholesterol, and to investigate how well the National Cholesterol Education Program Adult Treatment Panel III (ATP III) classification method represents risk of MI among hypertensives. METHODS: A population-based, case-control study of patients aged 30 to 79 years enrolled in a health maintenance organization, treated pharmacologically for hypertension, and who were not using lipid-lowering medication. Cases were diagnosed with an incident fatal or nonfatal MI between 1986 and 2000 (n = 1535). Controls were randomly sampled and frequency-matched to cases by sex, 10-year age category, and year of event (n = 3743). Subjects' most recent total cholesterol values were categorized according to ATP III guidelines. RESULTS: Overall, 31% (95% confidence interval: 23-39) of incident MIs among hypertensives could be explained by total cholesterol level above the optimal level of 200 mg/dL. Among participants in the highest ATP III risk stratum, 41% (95% confidence interval: 9-62) of the incident MIs were attributable to total cholesterol levels >160 mg/dL, but total cholesterol >or=200 mg/dL accounted for the majority of these excess events. CONCLUSIONS: The ATP III risk stratification approach improves detection of the CHD burden due to elevated total cholesterol among hypertensives at highest risk. A strategy to improve cholesterol control in hypertensive patients might prevent a substantial part of the burden of morbidity and mortality from MI.     

Alcohol consumption and risk of coronary heart disease in older adults: the Cardiovascular Health Study

OBJECTIVES: To evaluate several aspects of the relationship between alcohol use and coronary heart disease in older adults, including beverage type, mediating factors, and type of outcome. DESIGN: Prospective cohort study. SETTING: Four U.S. communities. PARTICIPANTS: Four thousand four hundred ten adults aged 65 and older free of cardiovascular disease at baseline. MEASUREMENTS: Risk of incident myocardial infarction or coronary death according to self-reported consumption of beer, wine, and spirits ascertained yearly. RESULTS: During an average follow-up period of 9.2 years, 675 cases of incident myocardial infarction or coronary death occurred. Compared with long-term abstainers, multivariate relative risks of 0.90 (95% confidence interval (CI)=0.71-1.14), 0.93 (95% CI=0.73-1.20), 0.76 (95% CI=0.53-1.10), and 0.58 (95% CI=0.39-0.86) were found in consumers of less than one, one to six, seven to 13, and 14 or more drinks per week, respectively (P for trend=.007). Associations were similar for secondary coronary outcomes, including nonfatal and fatal events. No strong mediators of the association were identified, although fibrinogen appeared to account for 9% to 10% of the relationship. The associations were statistically similar for intake of wine, beer, and liquor and generally similar in subgroups, including those with and without an apolipoprotein E4 allele. CONCLUSION: In this population, consumption of 14 or more drinks per week was associated with the lowest risk of coronary heart disease, although clinicians should not recommend moderate drinking to prevent coronary heart disease based on this evidence alone, because current National Institute on Alcohol Abuse and Alcoholism guidelines suggest that older adults limit alcohol intake to one drink per day.     

Use of calcium channel blockers and risk of hospitalized gastrointestinal tract bleeding

BACKGROUND: We conducted a case-control study of the association between calcium channel blocker use and gastrointestinal (GI) tract bleeding in hypertensive members of a health maintenance organization. METHODS: Case patients (n=174) were treated hypertensive health maintenance organization members hospitalized for GI tract bleeding between January 1992 and December 1994. Case patients were identified using computerized diagnosis codes and were confirmed by medical record review. Control subjects (n=771) were treated hypertensive members selected from ongoing studies at the health maintenance organization. Computerized pharmacy data and medical records were used to assess medication use and other risk factors for GI tract bleeding. RESULTS: Compared with beta-blocker users, calcium channel blocker users had an age-, sex- and calendar year-adjusted relative risk (RR) of GI tract bleeding of 2.60 (95% confidence interval [CI], 1.71-3.96). The RR associated with calcium channel blocker use was 2.05 (95% CI, 1.33-3.17) after further adjustment for number of recent visits, diastolic blood pressure, chronic congestive heart failure, and duration of hypertension. No significant dose-response relationship was observed. Compared with beta-blocker users, angiotensin-converting enzyme inhibitor users had an RR of 1.22 (95% CI, 0.75-1.97). Calcium channel blocker use tended to be more strongly associated with risk of lower GI tract bleeding (RR, 2.56; 95% CI, 1.08-6.05) than with risk of upper GI tract bleeding (RR, 1.54; 95% CI, 0.91-2.59) or peptic ulcer-related bleeding (RR, 1.17; 95% CI, 0.62-2.21), although these results were compatible with chance. CONCLUSIONS: Calcium channel blocker use might be associated with an elevated risk of GI tract bleeding. These findings require confirmation in randomized studies.     

Cystatin-C and inflammatory markers in the ambulatory elderly

Purpose

Inflammatory factors are elevated in persons with severe renal dysfunction, but their association across all levels of renal function is unclear. We compared cystatin-C, a novel marker of renal function, with creatinine and estimated glomerular filtration rate (eGFR) as predictors of C-reactive protein and fibrinogen levels.

Methods

This study is a cross-sectional analysis to evaluate cystatin-C, creatinine, and eGFR as predictors of the inflammatory markers C-reactive protein and fibrinogen. Participants included 4637 ambulatory elderly patients from the Cardiovascular Health Study. Multivariate linear regression was used to determine the independent associations of each renal function measurement with the inflammatory marker outcomes.

Results

After adjustment for confounding factors, cystatin-C was correlated with both C-reactive protein (coefficient = 0.13; 95% confidence interval: 0.10-1.16, P <.0001) and fibrinogen levels (0.15; 0.13-0.18, P <.0001). Associations were larger than those for creatinine and C-reactive protein (0.05; 0.02-0.07, P = .003) or fibrinogen (0.07; 0.04-0.10, P <.0001). Adjusted levels of C-reactive protein increased incrementally across quintiles of cystatin-C, from a median of 2.2 mg/L in quintile 1 to 3.7 mg/L in quintile 5. In contrast, both C-reactive protein and fibrinogen had U-shaped associations with quintiles of creatinine and eGFR, because the inflammatory markers were equivalently elevated in quintiles 1 and 5.

Conclusions

The finding of a significant linear association of cystatin-C and inflammation markers suggests that even small reductions in renal function may be associated with adverse pathophysiologic consequences.