David Nanchen

Meta-analysis: Subclinical Thyroid Dysfunction and the Risk for Coronary Heart Disease and Mortality

Context Is subclinical thyroid dysfunction associated with increased risk for coronary heart disease and mortality? Contribution This systematic review of 12 prospective cohort studies found that both subclinical hypothyroidism and hyperthyroidism were possibly associated with a small increased risk for coronary heart disease and mortality. Caution Data were uncertain. Confidence intervals around risk estimates were wide, particularly for those related to subclinical hyperthyroidism. Higher-quality studies showed lower estimates of risk than lower-quality studies. Implication Randomized trials testing the efficacy of thyroxine replacement and antithyroid medications for subclinical hypothyroidism and subclinical hyperthyroidism are needed. The Editors Subclinical thyroid dysfunction refers to patients who have an abnormal thyrotropin (thyroid-stimulating hormone [TSH]) level and a normal free thyroxine (T4) level (1). The prevalence of subclinical hypothyroidism is about 4.3% in adults (0.7% for subclinical hyperthyroidism), and prevalence is higher in older adults and women (25). Controversy persists about whether screening and treating subclinical thyroid dysfunction is warranted (1, 57) because current evidence about the risks is limited (1, 5) and randomized, controlled trials on relevant clinical outcomes have not been done (5, 8). Subclinical hypothyroidism has been associated with elevated cholesterol levels (911) and increased risk for atherosclerosis (12, 13). Yet, data on the relationship between subclinical hypothyroidism and coronary heart disease (CHD) events are conflicting (12, 1417). In a previous meta-analysis (18), we found that subclinical hypothyroidism was associated with a 1.65-fold increased risk (CI, 1.28 to 2.12) for CHD. However, that meta-analysis included several cross-sectional and casecontrol studies and only 5 small prospective studies. Recently, 3 large prospective studies on this issue have been published (14, 16, 17), with somewhat inconsistent results. Because these new data include many additional CHD events, data are now sufficient to do a meta-analysis that includes only prospective studies, which provide greater validity. Data on the association between subclinical hypothyroidism and mortality are also conflicting (14, 17, 19, 20). The consequences of subclinical hyperthyroidism have been less frequently studied than those of subclinical hypothyroidism. Subclinical hyperthyroidism has been associated with cardiovascular and total mortality (15), but with conflicting data (14, 17). Two of the 3 recent, large prospective studies (14, 17) also examined CHD and mortality in subclinical hyperthyroid participants. To summarize prospective evidence about the relationship between subclinical thyroid dysfunction and CHD and mortality, we did a systematic review of prospective cohort studies. Methods We followed a standardized protocol and conducted and reported this analysis according to the guidelines of the Meta-analysis Of Observational Studies in Epidemiology group (21). Data Sources and Searches We conducted a systematic literature search of MEDLINE for articles in any language on the association between subclinical thyroid dysfunction (both subclinical hypothyroidism and hyperthyroidism) and CHD or mortality (cardiovascular and total) published from 1950 to January 2008. To avoid missing any relevant study, we also searched the bibliographies of key articles in the field and those included in this review. We did our search on an Ovid (MEDLINE) server by using broadly defined Medical Subject Headings, such as thyroid diseases, hypothyroidism, hyperthyroidism, thyroid hormones, thyrotropin, mortality, myocardial ischemia, survival, and cardiovascular diseases and such keywords as subclinical hypothyroidism, subclinical hyperthyroidism, subclinical dysthyroidism, and subclinical thyroid, combined with the filter designed by knowledge information specialists from BMJ to select prospective studies (MEDLINE cohort-study filter) (22) but without their year limitation. Study Selection Two reviewers independently screened the abstracts and titles of the search results and eliminated articles only if they did not clearly study the association between subclinical thyroid dysfunction and CHD or mortality (cardiovascular or total) in a prospective design. The same 2 reviewers independently evaluated the remaining full-text articles for eligibility on the basis of a predefined set of eligibility criteria. Disagreements were resolved by consensus. We included only full-text, published, longitudinal cohort studies that measured thyroid function and followed persons prospectively, assessed CHD or mortality, and provided risk estimates or sufficient data to calculate risk estimates associated with subclinical thyroid dysfunction compared with normal thyroid function. Subclinical hypothyroidism was defined as elevated TSH levels and normal T4 levels (1). Several reviews suggest a TSH upper limit cutoff of 4.5 to 5.0 mU/L (1, 5), but others suggest decreasing the upper limit of the TSH range to 2.5 to 3.0 mU/L (23, 24). In the absence of consensus, we did not prespecify a TSH cutoff value to define subclinical hypothyroidism and did a sensitivity analysis by limiting the analysis to studies with a TSH cutoff of 4.5 mU/L or greater (5). Because most adults with elevated TSH levels have subclinical and not overt hypothyroidism (2), we included 2 studies with participants who had elevated TSH levels without a T4 measurement report (25, 26) and did a sensitivity analysis excluding those studies. For subclinical hyperthyroidism, we did not specify a TSH cutoff value (in the absence of consensus), but all studies had a cutoff value close to 0.3 to 0.5 mU/L. We included 1 study with participants who had low TSH levels without a reported T4 measurement (26) and did a sensitivity analysis excluding this study. For CHD, we considered myocardial infarction, angina, the acute coronary syndrome, revascularization (coronary artery surgery, percutaneous transluminal coronary angioplasty), and significant coronary stenosis (defined as 50%) (27). We also considered death due to CHD or cardiovascular disease and did a sensitivity analysis excluding studies that only included the latter. We assessed methods and criteria used for adjudication of those outcomes. The agreement between the 2 reviewers was 99.5% for the first screen (titles and abstracts; = 0.79) and 100% for the full-text screen (= 1.00). Data Extraction and Quality Assessment Two reviewers independently abstracted data on participant characteristics, criteria used to define subclinical thyroid dysfunction, CHD and mortality data, and study results with adjustment factors by using a standardized data collection form. Discrepancies in data extraction between reviewers were resolved by consensus. We systematically assessed key indicators of study quality (28): methods of outcome adjudication and ascertainment that account for confounders and completeness of follow-up ascertainment. Similar to our previous meta-analysis (18), study populations were considered either a convenience or a population-based sample (defined as a random sample of the general population) (29). Methods of outcome adjudication were categorized as use of formal adjudication procedures and adjudication without knowledge of thyroid status. A formal adjudication procedure was defined as having clear criteria for the outcomes that were reviewed by experts for each potential case (29) (for example, specific electrocardiogram or cardiac enzyme modifications for CHD). We did not consider CHD adjudication based only on death certificates as a formal adjudication procedure. If an article did not clearly mention 1 of these criteria, we considered that it had not been done. We contacted the authors of 7 studies (12, 14, 15, 19, 26, 30, 31) that met inclusion criteria but did not provide specific data on the associations between subclinical thyroid dysfunction and CHD or mortality. We obtained risk estimates and CIs for cardiovascular and total mortality from cohort studies in the United Kingdom (15) and the Netherlands (19), as well as specific data for CHD mortality from a cohort of cardiac patients in Italy (31). Authors of a cohort study that published data about the relationship between autoimmune thyroid disease and CHD (30) provided us with data specific to subclinical hypothyroidism that were available for a subgroup of the participants. Three studies provided us with specific numbers of outcomes in each thyroid group (12, 14, 26). We used the most adjusted risk estimates available (the model containing the greatest number of covariates), unless a separate model further adjusted for thyroid antibodies, because thyroid autoimmunity has been hypothesized to be a mediator in the association between subclinical hypothyroidism and CHD (20). We did a sensitivity analysis without the studies that adjusted for cholesterol because high cholesterol might be on the causal pathway. When risk estimates and CIs were not provided but raw data were available (25, 30, 32), we calculated relative risks (RRs) and CIs by using the Woolf method (3335). Data Synthesis and Analysis We first qualitatively synthesized data, paying particular attention to which definitions of subclinical thyroid dysfunction were used and which outcomes were measured. To calculate summary estimates and CIs of the risk for subclinical thyroid dysfunction, we pooled both RRs and hazard ratios (HRs) by using random-effects models based on the variance model developed by DerSimonian and Laird (36). Analyses were repeated by using fixed-effects models for comparison. The presence of heterogeneity across studies was evaluated by using the Q statistic with a conservative P value of 0.10 (37). We also calculated the I 2 statistic, which describes the total variation across studies attributable to heterogeneity rather than chance; an I

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.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. # Clinical Perspective {#article-title-42}

Subclinical Thyroid Dysfunction and the Risk of Heart Failure in Older Persons at High Cardiovascular Risk

CONTEXT Subclinical thyroid dysfunction is common in older people. However, its clinical importance is uncertain. OBJECTIVE Our objective was to determine the extent to which subclinical hyperthyroidism and hypothyroidism influence the risk of heart failure and cardiovascular diseases in older people. SETTING AND DESIGN The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) is an prospective cohort study. PATIENTS Patients included men and women aged 70-82 yr (n=5316) with known cardiovascular risk factors or previous cardiovascular disease. MAIN OUTCOME MEASURES Incidence rate of heart failure hospitalization, atrial fibrillation, and cardiovascular events and mortality according to baseline thyroid status were evaluated. Euthyroid participants (TSH=0.45-4.5 mIU/liter) were compared with those with subclinical hyperthyroidism (TSH<0.45 mIU/liter) and those with subclinical hypothyroidism (TSH≥4.5 mIU/liter, both with normal free T4). RESULTS Subclinical hyperthyroidism was present in 71 participants and subclinical hypothyroidism in 199 participants. Over 3.2 yr follow-up, the rate of heart failure was higher for subclinical hyperthyroidism compared with euthyroidism [age- and sex-adjusted hazard ratio (HR)=2.93, 95% confidence interval (CI)=1.37-6.24, P=0.005; multivariate-adjusted HR=3.27, 95% CI=1.52-7.02, P=0.002). Subclinical hypothyroidism (only at threshold>10 mIU/liter) was associated with heart failure (age- and sex-adjusted HR=3.01, 95% CI=1.12-8.11, P=0.029; multivariate HR=2.28, 95% CI=0.84-6.23). There were no strong evidence of an association between subclinical thyroid dysfunction and cardiovascular events or mortality, except in those with TSH below 0.1 or over 10 mIU/liter and not taking pravastatin. CONCLUSION Older people at high cardiovascular risk with low or very high TSH along with normal free T4 appear at increased risk of incident heart failure.

Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors

Aims Systemic levels of trimethylamine N-oxide (TMAO), a pro-atherogenic and pro-thrombotic metabolite produced from gut microbiota metabolism of dietary trimethylamine (TMA)-containing nutrients such as choline or carnitine, predict incident cardiovascular event risks in stable primary and secondary prevention subjects. However, the prognostic value of TMAO in the setting of acute coronary syndromes (ACS) remains unknown. Methods and results We investigated the relationship of TMAO levels with incident cardiovascular risks among sequential patients presenting with ACS in two independent cohorts. In the Cleveland Cohort, comprised of sequential subjects (n = 530) presenting to the Emergency Department (ED) with chest pain of suspected cardiac origin, an elevated plasma TMAO level at presentation was independently associated with risk of major adverse cardiac events (MACE, including myocardial infarction, stroke, need for revascularization, or death) over the ensuing 30-day (4th quartile (Q4) adjusted odds ratio (OR) 6.30, 95% confidence interval (CI), 1.89-21.0, P < 0.01) and 6-month (Q4 adjusted OR 5.65, 95%CI, 1.91-16.7; P < 0.01) intervals. TMAO levels were also a significant predictor of the long term (7-year) mortality (Q4 adjusted HR 1.81, 95%CI, 1.04-3.15; P < 0.05). Interestingly, TMAO level at initial presentation predicted risk of incident MACE over the near-term (30 days and 6 months) even among subjects who were initially negative for troponin T (< 0.1 ng/mL) (30 days, Q4 adjusted OR 5.83, 95%CI, 1.79-19.03; P < 0.01). The prognostic value of TMAO was also assessed in an independent multicentre Swiss Cohort of ACS patients (n = 1683) who underwent coronary angiography. Trimethylamine N-oxide again predicted enhanced MACE risk (1-year) (adjusted Q4 hazard ratios: 1.57, 95% CI, 1.03-2.41; P <0.05). Conclusion Plasma TMAO levels among patients presenting with chest pain predict both near- and long-term risks of incident cardiovascular events, and may thus provide clinical utility in risk stratification among subjects presenting with suspected ACS.

Prevalence and management of familial hypercholesterolaemia in patients with acute coronary syndromes.

AIMS We aimed to assess the prevalence and management of clinical familial hypercholesterolaemia (FH) among patients with acute coronary syndrome (ACS). METHODS AND RESULTS We studied 4778 patients with ACS from a multi-centre cohort study in Switzerland. Based on personal and familial history of premature cardiovascular disease and LDL-cholesterol levels, two validated algorithms for diagnosis of clinical FH were used: the Dutch Lipid Clinic Network algorithm to assess possible (score 3-5 points) or probable/definite FH (>5 points), and the Simon Broome Register algorithm to assess possible FH. At the time of hospitalization for ACS, 1.6% had probable/definite FH [95% confidence interval (CI) 1.3-2.0%, n = 78] and 17.8% possible FH (95% CI 16.8-18.9%, n = 852), respectively, according to the Dutch Lipid Clinic algorithm. The Simon Broome algorithm identified 5.4% (95% CI 4.8-6.1%, n = 259) patients with possible FH. Among 1451 young patients with premature ACS, the Dutch Lipid Clinic algorithm identified 70 (4.8%, 95% CI 3.8-6.1%) patients with probable/definite FH, and 684 (47.1%, 95% CI 44.6-49.7%) patients had possible FH. Excluding patients with secondary causes of dyslipidaemia such as alcohol consumption, acute renal failure, or hyperglycaemia did not change prevalence. One year after ACS, among 69 survivors with probable/definite FH and available follow-up information, 64.7% were using high-dose statins, 69.0% had decreased LDL-cholesterol from at least 50, and 4.6% had LDL-cholesterol ≤1.8 mmol/L. CONCLUSION A phenotypic diagnosis of possible FH is common in patients hospitalized with ACS, particularly among those with premature ACS. Optimizing long-term lipid treatment of patients with FH after ACS is required.

Prognostic value of PCSK9 levels in patients with acute coronary syndromes.

AIMS Proprotein convertase subtilisin kexin 9 (PCSK9) is an emerging target for the treatment of hypercholesterolaemia, but the clinical utility of PCSK9 levels to guide treatment is unknown. We aimed to prospectively assess the prognostic value of plasma PCSK9 levels in patients with acute coronary syndromes (ACS). METHODS AND RESULTS Plasma PCSK9 levels were measured in 2030 ACS patients undergoing coronary angiography in a Swiss prospective cohort. At 1 year, the association between PCSK9 tertiles and all-cause death was assessed adjusting for the Global Registry of Acute Coronary Events (GRACE) variables, as well as the achievement of LDL cholesterol targets of <1.8 mmol/L. Patients with higher PCSK9 levels at angiography were more likely to have clinical familial hypercholesterolaemia (rate ratio, RR 1.21, 95% confidence interval, CI 1.09-1.53), be treated with lipid-lowering therapy (RR 1.46, 95% CI 1.30-1.63), present with longer time interval of chest pain (RR 1.29, 95% CI 1.09-1.53) and higher C-reactive protein levels (RR 1.22, 95% CI 1.16-1.30). PCSK9 increased 12-24 h after ACS (374 ± 149 vs. 323 ± 134 ng/mL, P < 0.001). At 1 year follow-up, HRs for upper vs. lower PCSK9-level tertiles were 1.13 (95% CI 0.69-1.85) for all-cause death and remained similar after adjustment for the GRACE score. Patients with higher PCSK9 levels were less likely to reach the recommended LDL cholesterol targets (RR 0.81, 95% CI 0.66-0.99). CONCLUSION In ACS patients, high initial PCSK9 plasma levels were associated with inflammation in the acute phase and hypercholesterolaemia, but did not predict mortality at 1 year.

Prognosis of Patients With Familial Hypercholesterolemia After Acute Coronary Syndromes

BACKGROUND: Patients with heterozygous familial hypercholesterolemia (FH) and coronary heart disease have high mortality rates. However, in an era of high-dose statin prescription after acute coronary syndrome (ACS), the risk of recurrent coronary and cardiovascular events associated with FH might be mitigated. We compared coronary event rates between patients with and without FH after ACS. METHODS: We studied 4534 patients with ACS enrolled in a multicenter, prospective cohort study in Switzerland between 2009 and 2013 who were individually screened for FH on the basis of clinical criteria according to 3 definitions: the American Heart Association definition, the Simon Broome definition, and the Dutch Lipid Clinic definition. We used Cox proportional models to assess the 1-year risk of first recurrent coronary events defined as coronary death or myocardial infarction and adjusted for age, sex, body mass index, smoking, hypertension, diabetes mellitus, existing cardiovascular disease, high-dose statin at discharge, attendance at cardiac rehabilitation, and the GRACE (Global Registry of Acute Coronary Events) risk score for severity of ACS. RESULTS: At the 1-year follow-up, 153 patients (3.4%) had died, including 104 (2.3%) of fatal myocardial infarction. A further 113 patients (2.5%) experienced nonfatal myocardial infarction. The prevalence of FH was 2.5% with the American Heart Association definition, 5.5% with the Simon Broome definition, and 1.6% with the Dutch Lipid Clinic definition. Compared with patients without FH, the risk of coronary event recurrence after ACS was similar in patients with FH in unadjusted analyses, although patients with FH were >10 years younger. However, after multivariable adjustment including age, the risk was greater in patients with FH than without, with an adjusted hazard ratio of 2.46 (95% confidence interval, 1.07–5.65; P=0.034) for the American Heart Association definition, 2.73 (95% confidence interval, 1.46–5.11; P=0.002) for the Simon Broome definition, and 3.53 (95% confidence interval, 1.26–9.94; P=0.017) for the Dutch Lipid Clinic definition. Depending on which clinical definition of FH was used, between 94.5% and 99.1% of patients with FH were discharged on statins and between 74.0% and 82.3% on high-dose statins. CONCLUSIONS: Patients with FH and ACS have a >2-fold adjusted risk of coronary event recurrence within the first year after discharge than patients without FH despite the widespread use of high-intensity statins.

Resting heart rate and incident heart failure and cardiovascular mortality in older adults: role of inflammation and endothelial dysfunction: the PROSPER study

Resting heart rate is a promising modifiable cardiovascular risk marker in older adults, but the mechanisms linking heart rate to cardiovascular disease are not fully understood. We aimed to assess the association between resting heart rate and incident heart failure (HF) and cardiovascular mortality, and to examine whether these associations might be attributable to systemic inflammation and endothelial dysfunction.

Alcohol drinking, the metabolic syndrome and diabetes in a population with high mean alcohol consumption.

Diabet. Med. 27, 1241–1249 (2010)

Safety profile of prasugrel and clopidogrel in patients with acute coronary syndromes in Switzerland

Objective To assess safety up to 1 year of follow-up associated with prasugrel and clopidogrel use in a prospective cohort of patients with acute coronary syndromes (ACS). Methods Between 2009 and 2012, 2286 patients invasively managed for ACS were enrolled in the multicentre Swiss ACS Bleeding Cohort, among whom 2148 patients received either prasugrel or clopidogrel according to current guidelines. Patients with ST-elevation myocardial infarction (STEMI) preferentially received prasugrel, while those with non-STEMI, a history of stroke or transient ischaemic attack, age ≥75 years, or weight <60 kg received clopidogrel or reduced dose of prasugrel to comply with the prasugrel label. Results After adjustment using propensity scores, the primary end point of clinically relevant bleeding events (defined as the composite of Bleeding Academic Research Consortium, BARC, type 3, 4 or 5 bleeding) at 1 year, occurred at a similar rate in both patient groups (prasugrel/clopidogrel: 3.8%/5.5%). Stratified analyses in subgroups including patients with STEMI yielded a similar safety profile. After adjusting for baseline variables, no relevant differences in major adverse cardiovascular and cerebrovascular events were observed at 1 year (prasugrel/clopidogrel: cardiac death 2.6%/4.2%, myocardial infarction 2.7%/3.8%, revascularisation 5.9%/6.7%, stroke 1.0%/1.6%). Of note, this study was not designed to compare efficacy between prasugrel and clopidogrel. Conclusions In this large prospective ACS cohort, patients treated with prasugrel according to current guidelines (ie, in patients without cerebrovascular disease, old age or underweight) had a similar safety profile compared with patients treated with clopidogrel. Clinical trial registration number SPUM-ACS: NCT01000701; COMFORTABLE AMI: NCT00962416.