Statin-Associated Muscle Symptoms Among New Statin Users Randomly Assigned to Vitamin D or Placebo.

Importance: Statin-associated muscle symptoms (SAMS) are common and may lead to discontinuation of indicated statin therapy. Observational studies suggest that vitamin D therapy is associated with reduced statin intolerance, but no randomized studies have been reported. Objective: To test whether vitamin D supplementation was associated with prevention of SAMS and a reduction of statin discontinuation. Design, Setting, and Participants: Men 50 years or older and women 55 years or older, free of cancer and cardiovascular disease, were enrolled in a randomized, placebo-controlled, double-blind clinical trial of vitamin D supplementation. Participants who initiated statin therapy after randomization were surveyed in early 2016. The data were analyzed in early 2022. Interventions: Daily cholecalciferol (2000 international units) or placebo with assessment of statin prescriptions during follow-up. Main Outcomes and Measures: Muscle pain or discomfort lasting several days (primary outcome) and discontinuation of a statin due to SAMS (secondary outcome). Results: Statins were initiated by 1033 vitamin D-assigned participants and 1050 placebo-assigned participants; mean (SD) age was 66.8 (6.2) years and 49% were women. Over 4.8 years of follow-up, SAMS were reported by 317 participants (31%) assigned vitamin D and 325 assigned placebo (31%). The adjusted odds ratio (OR) was 0.97 (95% CI, 0.80-1.18; P = .78). Statins were discontinued by 137 participants (13%) assigned to vitamin D and 133 assigned to placebo (13%) with an adjusted OR of 1.04 (95% CI, 0.80-1.35; P = .78). These results were consistent across pretreatment 25-hydroxy vitamin D levels (interaction P value = .83). Among participants with levels less than 20 ng/mL, SAMS were reported by 28 of 85 vitamin D-assigned participants (33%) and 33 of 95 placebo-assigned participants (35%). For those with levels less than 30 ng/ml, SAMS were reported by 88 of 330 vitamin-D assigned participants (27%) and 96 of 323 of placebo-assigned participants (30%). Conclusions and Relevance: Vitamin D supplementation did not prevent SAMS or reduce statin discontinuation. These results were consistent across pretreatment 25-hydroxy vitamin D levels. Trial Registration: ClinicalTrials.gov Identifier: NCT01169259.

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency.

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient's burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research.

Association of spontaneous bleeding and myocardial infarction with long-term mortality after percutaneous coronary intervention.

BACKGROUND: Platelet inhibition after percutaneous coronary intervention (PCI) reduces the risk of myocardial infarction (MI) but increases the risk of bleeding. MIs and bleeds during the index hospitalization for PCI are known to negatively affect long-term outcomes. The impact of spontaneous bleeding occurring after discharge on long-term mortality is unknown. OBJECTIVES: This study sought to examine, in a real-world cohort, the association between spontaneous major bleeding or MI after PCI and long-term mortality. METHODS: We conducted a retrospective cohort study of patients ≥30 years of age who underwent a PCI between 1996 and 2008 in an integrated healthcare delivery system. We used extended Cox regression to examine the associations of spontaneous bleeding and MI with all-cause mortality, after adjustment for time-updated demographics, comorbidities, periprocedural events, and longitudinal medication exposure. RESULTS: Among 32,906 patients who had a PCI and survived the index hospitalization, 530 had bleeds and 991 had MIs between 7 and 365 days post-discharge. There were 4,048 deaths over a mean follow-up of 4.42 years. The crude annual death rate after a spontaneous bleed (9.5%) or MI (7.6%) was higher than among patients who experienced neither event (2.6%). Bleeding was associated with an increased rate of death (adjusted hazard ratio [HR]: 1.61, 95% confidence interval [CI]: 1.30 to 2.00), similar to that after an MI (HR: 1.91; 95% CI: 1.62 to 2.25). The association of bleeding with death remained significant after additional adjustment for the longitudinal use of antiplatelet agents. CONCLUSIONS: Spontaneous bleeding after a PCI was independently associated with higher long-term mortality, and conveyed a risk comparable to that of an MI during follow-up. This tradeoff between efficacy and safety bolsters the argument for personalizing antiplatelet therapy after PCI on the basis of the patient's long-term risk of both thrombotic and bleeding events.

Acute kidney injury after CABG versus PCI: an observational study using 2 cohorts.

BACKGROUND: Acute kidney injury (AKI) is a known complication after coronary revascularization, but few studies have directly compared the incidence of AKI after coronary artery bypass surgery (CABG) or after percutaneous coronary intervention (PCI) in similar patients. OBJECTIVES: The aim of this study was to investigate whether multivessel CABG compared with PCI as an initial revascularization strategy is associated with a higher risk for AKI. METHODS: A retrospective analysis of patients undergoing first documented coronary revascularization was conducted using 2 complementary cohorts: 1) Kaiser Permanente Northern California, a diverse, integrated health care delivery system; and 2) Medicare beneficiaries, a large, nationally representative older cohort. AKI was defined in the Kaiser Permanente Northern California cohort by an increase in serum creatinine of ≥0.3 mg/dl or ≥150% above baseline and in the Medicare cohort by discharge diagnosis codes and the use of dialysis. RESULTS: The incidence of AKI was 20.4% in the Kaiser Permanente Northern California cohort and 6.2% in the Medicare cohort. The incidence of AKI requiring dialysis was <1%. CABG was associated with a 2- to 3-fold significantly higher adjusted odds for developing AKI compared with PCI in both cohorts. CONCLUSIONS: AKI is common after multivessel coronary revascularization and is more likely after CABG than after PCI. The risk for AKI should be considered when choosing a coronary revascularization strategy, and ways to prevent AKI after coronary revascularization are needed.

ß-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease.

BACKGROUND: The effectiveness of beta-blockers for preventing cardiac events has been questioned for patients who have coronary heart disease (CHD) without a prior myocardial infarction (MI). OBJECTIVES: The purpose of this study was to assess the association of beta-blockers with outcomes among patients with new-onset CHD. METHODS: We studied consecutive patients discharged after the first CHD event (acute coronary syndrome or coronary revascularization) between 2000 and 2008 in an integrated healthcare delivery system who did not use beta-blockers in the year before entry. We used time-varying Cox regression models to determine the hazard ratio (HR) associated with beta-blocker treatment and used treatment-by-covariate interaction tests (p(int)) to determine whether the association differed for patients with or without a recent MI. RESULTS: A total of 26,793 patients were included, 19,843 of whom initiated beta-blocker treatment within 7 days of discharge from their initial CHD event. Over an average of 3.7 years of follow-up, 6,968 patients had an MI or died. Use of beta-blockers was associated with an adjusted HR for mortality of 0.90 (95% confidence limits [CL]: 0.84 to 0.96), and an adjusted HR for death or MI of 0.92 (CL: 0.87 to 0.97). The association between beta-blockers and outcomes differed significantly between patients with and without a recent MI (HR for death: 0.85 vs. 1.02, p(int) = 0.007; and HR for death or MI: 0.87 vs. 1.03, p(int) = 0.005). CONCLUSIONS: Use of beta-blockers among patients with new-onset CHD was associated with a lower risk of cardiac events only among patients with a recent MI.

Incremental prognostic information from kidney function in patients with new onset coronary heart disease.

BACKGROUND: Prognostic factors are usually evaluated by their statistical significance rather than by their clinical utility. Risk reclassification measures the extent to which a novel marker adds useful information to a prognostic model. The extent to which estimated glomerular filtration rate (eGFR) adds information about prognosis among patients with coronary heart disease is uncertain. METHODS: We studied patients in an integrated health care delivery system with newly diagnosed coronary heart disease. We developed a model of the risk of death over 2 years of follow-up and then added eGFR to the model and measured changes in C-index, net reclassification improvement, and integrated discrimination improvement. RESULTS: Almost half of the 31,533 study patients had reduced eGFR (<60 mL/min per 1.73 m(2)). Mortality was significantly higher among patients who had lower levels of eGFR, even after adjustment for baseline characteristics (P < .0001). The addition of eGFR to the prognostic model increased the C-index from 0.837 to 0.843, the net reclassification improvement by 3.2% (P < .0001), and integrated discrimination improvement by 1.3% (P = .007). CONCLUSION: Estimated glomerular filtration rate is an informative prognostic factor among patients with incident coronary heart disease, independent of other clinical characteristics.

Transcatheter aortic valve replacement in nonsurgical candidates with severe, symptomatic aortic stenosis: a cost-effectiveness analysis.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) seems to improve the survival and quality of life of patients with aortic stenosis ineligible for surgical aortic valve replacement. METHODS AND RESULTS: We used a decision analytic Markov model to estimate lifetime costs and benefits in a hypothetical cohort of patients with severe, symptomatic aortic stenosis who were ineligible for surgical aortic valve replacement. The model compared transfemoral TAVR with medical management and was calibrated to the Placement of Aortic Transcatheter Valves (PARTNER) trial. TAVR increased life expectancy from 2.08 to 2.93 years and quality-adjusted life expectancy from 1.19 to 1.93 years. TAVR also reduced subsequent hospitalizations by 1.40 but increased complications, particularly stroke (from 1% to 11% lifetime risk), and also increased lifetime costs from $83,600 to $169,100. The incremental cost-effectiveness of TAVR was $116,500 per quality-adjusted life-year gained ($99,900 per life-year gained). Results were robust to reasonable changes in individual variables but were sensitive to the level of annual healthcare costs caused by noncardiac diseases and to the projected life expectancy of medically treated patients. CONCLUSIONS: TAVR seems to be an effective but somewhat expensive alternative to medical management among patients with symptomatic aortic stenosis ineligible for surgery. TAVR is more cost-effective for patients with a lower burden of noncardiac disease.

Comparative effectiveness of coronary artery bypass grafting and percutaneous coronary intervention for multivessel coronary disease in a community-based population with chronic kidney disease.

BACKGROUND: Randomized clinical trials comparing coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) have largely excluded patients with chronic kidney disease (CKD), leading to uncertainty about the optimal coronary revascularization strategy. We sought to test the hypothesis that an initial strategy of CABG would be associated with lower risks of long-term mortality and cardiovascular morbidity compared with PCI for the treatment of multivessel coronary heart disease in the setting of CKD. METHODS: We created a propensity score-matched cohort of patients aged ≥30 years with no prior dialysis or renal transplant who received multivessel coronary revascularization between 1996 and 2008 within a large integrated health care delivery system in northern California. We used extended Cox regression to examine death from any cause, acute coronary syndrome, and repeat revascularization. RESULTS: Coronary artery bypass grafting was associated with a significantly lower adjusted rate of death than PCI across all strata of estimated glomerular filtration rate (eGFR) (in mL/min per 1.73 m(2)): the adjusted hazard ratio (HR) was 0.81, 95% CI 0.68 to 1.00 for patients with eGFR ≥60; HR 0.73 (CI 0.56-0.95) for eGFR of 45 to 59; and HR 0.87 (CI 0.67-1.14) for eGFR <45. Coronary artery bypass grafting was also associated with significantly lower rates of acute coronary syndrome and repeat revascularization at all levels of eGFR compared with PCI. CONCLUSIONS: Among adults with and without CKD, multivessel CABG was associated with lower risks of death and coronary events compared with multivessel PCI.

Use of medications for secondary prevention after coronary bypass surgery compared with percutaneous coronary intervention.

OBJECTIVES: This study sought to compare use of evidence-based secondary preventive medications after coronary bypass surgery (CABG) and percutaneous coronary intervention (PCI). BACKGROUND: Use of cardioprotective medication after coronary revascularization has been inconsistent and relatively low in older studies. METHODS: We studied patients in a large integrated healthcare delivery system who underwent CABG or PCI for new onset coronary disease. We used data from health plan databases about prescriptions dispensed during the first year after initial coronary revascularization to identify patients who never filled a prescription and to calculate the medication possession ratio among patients who filled at least 1 prescription. We focused on angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARBs), beta-blockers, and statins. RESULTS: Between 2000 and 2007, 8,837 patients with new onset coronary disease underwent initial CABG, and 14,516 underwent initial PCI. Patients receiving CABG were more likely than patients receiving PCI to not fill a prescription for a statin (7.1% vs. 4.8%, p < 0.0001) or for an ACEI/ARB (29.1% vs. 22.4%, p < 0.0001), but similar proportions never filled a prescription for a beta-blocker (6.4% vs. 6.1%). Among those who filled at least 1 prescription post-revascularization, patients receiving CABG had lower medication possession ratios than patients receiving PCI for ACEI/ARBs (69.4% vs. 77.8%, p < 0.0001), beta-blockers (76.1% vs. 80.6%, p < 0.0001), and statins (82.7% vs. 84.2%, p < 0.001). CONCLUSIONS: Patients who received CABG were generally less likely than patients who received PCI to fill prescriptions for secondary preventive medications and to use those medications consistently in the first year after the procedure.

Incidental findings on cardiac multidetector row computed tomography among healthy older adults: prevalence and clinical correlates.

BACKGROUND: With the widespread use of cardiac multidetector row computed tomography (MDCT), the issue of incidental findings is receiving increasing attention. Our objectives were to evaluate the prevalence of incidental findings discovered during cardiac MDCT scanning and to identify clinical variables associated with incidental findings. METHODS: This cross-sectional analysis involved a population-based sample recruited from an integrated health care delivery system in Northern California as part of the Atherosclerotic Disease, Vascular Function and Genetic Epidemiology (ADVANCE) Study. Healthy men and women aged 60 to 69 years without diagnosed cardiovascular disease underwent cardiac MDCT for the detection and quantification of coronary artery calcification. The images were prospectively evaluated for incidental findings. RESULTS: A total of 459 participants underwent MDCT scanning, and the overall prevalence of any incidental finding was 41%. Of the 459 participants, 105 (23%) had at least 1 incidental finding that was recommended for clinical or radiological follow-up examination, the most common of which was single or multiple pulmonary nodules (18%). Participants with and without incidental findings had comparable baseline demographics and selected clinical variables, although there were significantly fewer men and a significantly lower prevalence of the metabolic syndrome in those with incidental findings. CONCLUSIONS: Incidental findings, especially pulmonary nodules, are common in cardiac MDCT performed to assess coronary artery calcification in older healthy adults. The net risks and benefits of looking for noncardiac abnormalities during cardiac MDCT should be rigorously evaluated.

Matrix metalloproteinase circulating levels, genetic polymorphisms, and susceptibility to acute myocardial infarction among patients with coronary artery disease.

OBJECTIVE: The aim of this study was to assess systematic differences between patients with acute myocardial infarction (MI) and patients with stable angina in matrix metalloproteinase (MMP) circulating levels and genetic polymorphisms. METHODS: We identified adults in a large integrated health care delivery system whose initial clinical presentation of coronary disease was either an acute MI or stable exertional angina. A total of 909 patients with acute MI, 466 patients with stable angina, and 1023 healthy older control subjects were genotyped. Serum levels of pro-MMP1, MMP2, MMP3, MMP9, and MMP10 were measured in 199 randomly selected patients from each group. RESULTS: At a median of 15 weeks after initial clinical presentation, higher circulating levels of MMP2 and MMP9 were independently associated with acute MI after statistical adjustment for conventional risk factors, hs-CRP levels, and cardiac medications. By contrast, none of the polymorphisms in MMP1, MMP2, MMP3, MMP9, or MMP10 was significantly associated with either acute MI compared with angina, or with coronary disease compared with controls. CONCLUSIONS: Circulating levels of MMP2 and MMP9 are independently associated with development of an acute MI rather than stable angina as the initial clinical presentation of coronary artery disease.

Plasma leptin levels and coronary artery calcification in older adults.

CONTEXT: Leptin is associated with adiposity and insulin resistance and may play a direct role in vascular calcification. It is unclear, however, whether leptin is an independent predictor of atherosclerotic burden. OBJECTIVE: The aim of this study was to examine the association between plasma leptin and coronary artery calcification (CAC) in an ethnically diverse cohort of older adult men and women free of clinical cardiovascular disease. DESIGN: This was a cross-sectional study with data collection between January 2002 and February 2004 as part of the ADVANCE Study. SETTING: The study was conducted at an integrated health care delivery system in Northern California. PARTICIPANTS: Participants included 949 men and women aged 60-69 yr old. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: The main outcome measure was CAC by multidetector row computed tomography. RESULTS: In ordinal logistic regression, plasma leptin levels were positively associated with extent of CAC independently of age, race/ethnicity, and smoking status in women (odds ratio of higher CAC for the sex-specific upper tertile vs. lower tertile = 1.81; 95% confidence interval, 1.10-3.00) but not in men (odds ratio = 1.29; 95% confidence interval = 0.89-1.86). However, this association was explained by metabolic risk factors and adiposity measures. CONCLUSIONS: Our findings support a role of leptin on vascular calcification in women but, in our sample of older adults, the association between leptin and CAC was not independent of other cardiac risk factors.

Cost-effectiveness as an outcome in randomized clinical trials.

BACKGROUND: Economic outcomes are now included in many contemporary randomized trials and provide an additional dimension to the assessment of interventions. Economic data collection and analysis pose several methodologic challenges, however. PURPOSE: This paper reviews methods of incorporating economic outcomes in clinical trials. RESULTS: Data on medical resource utilization and cost can readily be collected along with data on clinical outcomes. The cost of planned interventions can be measured with reasonable accuracy, but costs due to unplanned clinical events are more difficult to measure reliably. The total cost depends critically on these relatively infrequent, yet costly, adverse outcomes, which may partially, or even completely, offset any difference between the planned costs of the randomized therapies. Newer therapies are typically more expensive than older therapies, so the most important question is whether patient outcomes are improved sufficiently to justify the added expense. Cost-effectiveness analysis helps gauge the value provided by a new therapy. The cost-effectiveness of an intervention compared with an alternative is defined as the ratio of the incremental costs and the incremental clinical benefits, measured as dollars per quality-adjusted life-year added. The follow-up period in most clinical trials is generally long enough to measure the added cost of therapy, but may not capture the full benefits of treatment. The limited time horizon of clinical trials makes it necessary to use a model to extrapolate the observed effect of treatment and project the increase in life expectancy. The resulting cost-effectiveness ratio is sensitive to assumptions about the long-term efficacy of treatment, particularly whether the treatment effect will continue or dissipate over time. CONCLUSION: Economic outcomes can be measured alongside clinical outcomes in randomized trial. While the use of cost-effectiveness models falls outside the strictly empirical, within-trial analysis framework that is embraced by most clinical trialists, it provides an explicit approach to assessing whether the intervention under study provides a clinically meaningful improvement in outcome that is worthwhile.

Statin and beta-blocker therapy and the initial presentation of coronary heart disease.

BACKGROUND: Coronary atherosclerosis develops slowly over decades but is frequently characterized clinically by sudden unstable episodes. Patients who present with unstable coronary disease, such as acute myocardial infarction, may systematically differ from patients who present with relatively stable coronary disease, such as exertional angina. OBJECTIVE: To examine whether medication use or patient characteristics influence the mode of initial clinical presentation of coronary disease. DESIGN: Case-control study. SETTING: Large integrated health care delivery system in northern California. PATIENTS: Adults whose first clinical presentation of coronary disease was either acute myocardial infarction (n = 916) or stable exertional angina (n = 468). MEASUREMENTS: Use of cardiac medications before the event from pharmacy databases and demographic, lifestyle, and clinical characteristics from self-report and clinical and administrative databases. RESULTS: Compared with patients with incident stable exertional angina, patients with incident acute myocardial infarction were more likely to be men, smokers, physically inactive, and hypertensive but were less likely to have a parental history of coronary disease. Patients presenting with myocardial infarction were much less likely to have received statins (19.3% vs. 40.4%; P < 0.001) and beta-blockers (19.0% vs. 47.7%; P < 0.001) than patients presenting with exertional angina. After adjustment for potential confounders, recent use of statins (adjusted odds ratio, 0.45 [95% CI, 0.32 to 0.62]) and beta-blockers (adjusted odds ratio, 0.26 [CI, 0.19 to 0.35]) was associated with lower likelihoods of presenting with an acute myocardial infarction than with stable angina. LIMITATIONS: This observational study did not have information on all possible confounding factors, including use of aspirin therapy. CONCLUSION: Statin and beta-blocker use was associated with lower odds of presenting with an acute myocardial infarction than with stable angina. Additional studies are needed to confirm that these therapies protect against unstable, higher-risk clinical presentations of coronary disease.

Management of ventricular arrhythmias in diverse populations in California.

BACKGROUND: The use of coronary angiography and revascularization is lower than expected among black patients. It is uncertain whether use of other cardiac procedures also varies according to race and ethnicity and whether outcomes are affected. METHODS: We analyzed discharge abstracts from all nonfederal hospitals in California of patients hospitalized for a primary diagnosis of ventricular tachycardia or ventricular fibrillation between 1992 and 1994. We compared mortality rates and use of electrophysiologic study (EPS) and implantable cardioverter-defibrillator (ICD) procedures according to the race and ethnicity of the patient. RESULTS: Among 8713 patients admitted with ventricular tachycardia or ventricular fibrillation, 29% (n = 2508) had a subsequent EPS procedure, and 9% (n = 818) had an ICD implanted. After controlling for potential confounding factors, we found that black patients were significantly less likely than white patients to undergo EPS (odds ratio 0.72, CI 0.56-0.92) or ICD implantation (odds ratio 0.39, CI 0.25-0.60). Blacks discharged alive from the initial hospital admission had higher mortality rates over the next year than white patients, even after controlling for multiple confounding risk factors (risk ratio 1.18, CI 1.03-1.36). The use of EPS and ICD procedures was also significantly affected by several other factors, most notably by on-site procedure availability but also by age, sex, and insurance status. CONCLUSIONS: In a large population of patients hospitalized for ventricular arrhythmia, blacks had significantly lower rates of utilization for EPS and ICD procedures and higher subsequent mortality rates.