Subclinical Thyroid Dysfunction and the Risk of Heart Failure Events: An Individual Participant Data Analysis From 6 Prospective Cohorts

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.     

Comparison of bleeding and in-hospital mortality in Asian-Americans versus Caucasian-Americans with ST-elevation myocardial infarction receiving reperfusion therapy

Concern has been raised that Asian-Americans may have a higher bleeding risk than Caucasian-Americans when treated with fibrinolytic and antithrombotic agents. To date there is limited evidence to support or refute this hypothesis or evaluate bleeding risk and its related outcomes in Caucasian-Americans versus Asian-Americans with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary interventions (PPCI). We evaluated Asian-Americans and Caucasian-Americans with STEMI receiving reperfusion therapy in the National Registry of Myocardial Infarction (NRMI) 4 and 5 (n = 90,317). We studied risk-adjusted major bleeding and in-hospital mortality. Major bleeding rates after fibrinolysis were similar in Asian-Americans (n = 705) and Caucasian-Americans (n = 42,243, 11.1% vs 10.3%, adjusted odds ratio [OR] 0.97, 95% confidence interval [CI] 0.69 to 1.36, p = 0.5002). Although the observed major bleeding rate was higher in Asian-Americans (n = 1,037) compared to Caucasian-Americans (n = 46,332) treated with PPCI (10.3% vs 7.8%, p = 0.0036), these rates differed only marginally after adjusting for baseline clinical variables (OR 1.24, 95% CI 0.97 to 1.59). Overall adjusted mortality was similar in Asian-Americans and Caucasian-Americans when treated with fibrinolysis (OR 0.96, 95% CI 0.56 to 1.65) or with PPCI (OR 1.35, 95% CI 0.85 to 2.13). Major bleeding after PPCI or fibrinolysis was associated with similar increased risks for mortality in these ethic groups. In conclusion, despite suggestions to the contrary, Asian-Americans with STEMI treated with fibrinolysis or PPCI had similar bleeding and bleeding-related mortality risks compared to Caucasian-Americans. Given the genotypic and phenotypic differences between the 2 cohorts, similar studies in the rapidly growing Asian-American population are needed to confirm our findings and to understand the safety and effectiveness of newer potent antiplatelet and antithrombotic agents in patients with coronary syndromes.     

Candesartan-based therapy and risk of cancer in patients with systemic hypertension (Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease [HIJ-CREATE] substudy)

The aim of the present study was to clarify the influence of candesartan-based therapy on subsequent carcinogenesis and cancer death in patients with coronary artery disease with hypertension in a substudy of a multicenter, prospective, randomized, controlled trial. That trial compared the effects of candesartan-based therapy with those of non-angiotensin receptor blocker (ARB)-based standard therapy on major adverse cardiovascular events. Hypertensive patients with coronary artery disease were randomly assigned to receive either candesartan-based (n = 1,024) or non-ARB-based pharmacotherapy, including angiotensin-converting enzyme inhibitors (n = 1,025). During a median follow-up of 4.2 years, 1,606 adverse events (798 in the candesartan group and 808 in the non-ARB standard group) were reported. Among them, new cancer occurred in 5.37% of subjects in the candesartan group and 5.66% of subjects in the standard therapy group (hazard ratio 0.95, 95% confidence interval 0.65 to 1.38). Cancer deaths occurred in 1.66% in the candesartan group and 2.44% in the standard therapy group, respectively (hazard ratio 0.74, 95% confidence interval 0.39 to 1.39). Kaplan-Meier estimates of survival without new cancer and cancer deaths demonstrated that candesartan-based therapy does not accelerate the occurrence of new cancer (log-rank, p = 0.84) or cancer death (p = 0.39) compared to standard therapy. Advanced age and male gender were independently and significantly correlated with the subsequent incidence of cancer. In conclusion, the results of the present study suggest that candesartan-based therapy is not associated with either carcinogenesis or cancer death compared to non-ARB standard therapy.     

Association of frontal QRS-T angle--age risk score on admission electrocardiogram with mortality in patients admitted with an acute coronary syndrome

Risk assessment is central to the management of acute coronary syndromes. Often, however, assessment is not complete until the troponin concentration is available. Using 2 multicenter prospective observational studies (Evaluation of Methods and Management of Acute Coronary Events [EMMACE] 2, test cohort, 1,843 patients; and EMMACE-1, validation cohort, 550 patients) of unselected patients with acute coronary syndromes, a point-of-admission risk stratification tool using frontal QRS-T angle derived from automated measurements and age for the prediction of 30-day and 2-year mortality was evaluated. Two-year mortality was lowest in patients with frontal QRS-T angles <38° and highest in patients with frontal QRS-T angles >104° (44.7% vs 14.8%, p <0.001). Increasing frontal QRS-T angle-age risk (FAAR) scores were associated with increasing 30-day and 2-year mortality (for 2-year mortality, score 0 = 3.7%, score 4 = 57%; p <0.001). The FAAR score was a good discriminator of mortality (C statistics 0.74 [95% confidence interval 0.71 to 0.78] at 30 days and 0.77 [95% confidence interval 0.75 to 0.79] at 2 years), maintained its performance in the EMMACE-1 cohort at 30 days (C statistics 0.76 (95% confidence interval 0.71 to 0.8] at 30 days and 0.79 (95% confidence interval 0.75 to 0.83] at 2 years), in men and women, in ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction, and compared favorably with the Global Registry of Acute Coronary Events (GRACE) score. The integrated discrimination improvement (age to FAAR score at 30 days and at 2 years in EMMACE-1 and EMMACE-2) was p <0.001. In conclusion, the FAAR score is a point-of-admission risk tool that predicts 30-day and 2-year mortality from 2 variables across a spectrum of patients with acute coronary syndromes. It does not require the results of biomarker assays or rely on the subjective interpretation of electrocardiograms.     

Relation of improvement in estimated glomerular filtration rate with atorvastatin to reductions in hospitalizations for heart failure (from the Treating to New Targets [TNT] study)

Impaired kidney function often accompanies heart failure (HF) and is associated with a worse prognosis. This post hoc analysis of the Treating to New Targets (TNT) trial examined whether the observed decrease in HF hospitalizations with high- compared to low-dose atorvastatin could be related to improvements in kidney function. Of 10,001 TNT participants, 9,376 had estimated glomerular filtration rate (eGFR) measurements at baseline and 1 year and were included in this analysis. The association of change in year-1 eGFR and subsequent HF hospitalization was examined using Cox regression models. In total 218 participants developed subsequent HF hospitalization. Little change in eGFR occurred over 1 year in the atorvastatin 10-mg group, whereas eGFR improved in the 80-mg group by 1.48 ml/min/1.73 m(2) (95% confidence interval 1.29 to 1.67, p <0.0001). Subsequent HF was preceded by a decrease in eGFR over 1 year compared to modest improvement in those without subsequent HF (-0.09 ± 7.89 vs 0.81 ± 6.90 ml/min/1.73 m(2), p = 0.0015). After adjusting for baseline eGFR, each 5-ml/min/1.73 m(2) increase in eGFR at 1 year was associated with a lower risk of subsequent HF hospitalization (hazard ratio 0.85, 95% confidence interval 0.77 to 0.94, p = 0.002). This relation was independent of treatment effect or change in low-density lipoprotein cholesterol level at 1 year. In conclusion, treatment with high- compared to low-dose atorvastatin was associated with improvement in eGFR at 1 year, which was related to a decrease in subsequent HF hospitalization. This suggests that improvement in kidney function may be related to the beneficial effect of high-dose atorvastatin on HF hospitalization.     

Impact of statin therapy on late target lesion revascularization after sirolimus-eluting stent implantation (from the CREDO-Kyoto Registry Cohort-2)

Therapeutic strategies preventing late target lesion revascularization (TLR) after drug-eluting stent implantation have not been yet adequately investigated. In 13,087 consecutive patients undergoing first percutaneous coronary intervention in the CREDO-Kyoto Registry Cohort-2, we identified 10,221 patients who were discharged alive after implantation of sirolimus-eluting stents (SESs) only (SES stratum 5,029) or bare-metal stents (BMSs) only (BMS stratum 5,192). Impact of statin therapy at time of discharge from the index hospitalization on early (within the first year) and late (1 year to 4 years) TLR, was assessed in the SES stratum (statin group 2,735; nonstatin group 2,294) and in the BMS stratum (statin group 2,576; nonstatin group 2,616). Despite a significantly lower incidence of early TLR (7.8% vs 22.2%, p <0.0001), SES use compared to BMS use was associated with a significantly higher incidence of late TLR (7.7% vs 3.0%, p <0.0001). In the SES and BMS strata, the incidence of early TLR was similar regardless of statin use. In the SES stratum, the incidence of late TLR was significantly lower in the statin group than in the nonstatin group (6.1% vs 9.6%, p = 0.002), whereas no significant difference was found in the BMS stratum (2.6% vs 3.3%, p = 0.38). After adjusting confounders, risk for late TLR significantly favored statin use in the SES stratum (hazard ratio 0.73, 95% confidence interval 0.54 to 0.98, p = 0.04), whereas the risk decrease was not significant in the BMS stratum (hazard ratio 0.74, 95% confidence interval 0.46 to 1.20, p = 0.23). In conclusion, statin therapy at hospital discharge was associated with a significantly lower risk for late TLR after SES implantation.