Carcinoid Heart Disease: Prognostic Value of 5-Hydroxyindoleacetic Acid Levels and Impact on Survival: A Systematic Literature Review.

BACKGROUND: Carcinoid heart disease (CHD) can develop in patients with carcinoid syndrome (CS), itself caused by overproduction of hormones and other products from some neuroendocrine tumours. The most common hormone is serotonin, detected as high 5-hydroxyindoleacetic acid (5-HIAA). This systematic literature review summarises current literature on the impact of CHD on survival, and the relationship between 5-HIAA levels and CHD development, progression, and mortality. METHODS: MEDLINE, Embase, Cochrane databases, and grey literature were searched using terms for CHD, 5-HIAA, disease progression, and mortality/survival. Eligible articles were non-interventional and included patients with CS and predefined CHD and 5-HIAA outcomes. RESULTS: Publications reporting on 31 studies were included. The number and disease states of patients varied between studies. Estimates of CHD prevalence and incidence among patients with a diagnosis/symptoms indicative of CS were 3-65% and 3-42%, respectively. Most studies evaluating survival found significantly higher mortality rates among patients with versus without CHD. Patients with CHD reportedly had higher 5-HIAA levels; median urinary levels in patients with versus without CHD were 266-1,381 versus 67.5-575 µmol/24 h. Higher 5-HIAA levels were also found to correlate with disease progression (median progression/worsening-associated levels: 791-2,247 µmol/24 h) and increased odds of death (7% with every 100 nmol/L increase). CONCLUSIONS: Despite the heterogeneity of studies, the data indicate that CHD reduces survival, and higher 5-HIAA levels are associated with CHD development, disease progression, and increased risk of mortality; 5-HIAA levels should be carefully managed in these patients.

Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study.

Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2. Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated. Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm. Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. Clinical Trial Number: NCT00412061, www.clinicaltrials.gov.

The Influence of Preoperative Symptoms on the Death of Patients with Small Intestinal Neuroendocrine Tumors.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are uncommon tumors with an annual incidence of about 1 per 100,000. Usually, SI-NETs have a slow progression, and patients often present with generalized disease. Many patients do well, and the disease has a relatively favorable 5-year survival rate. Some SI-NETs, however, have a more negative prognosis. This study aimed to establish prognostic factors for death identifiable at primary surgery. METHODS: A nested case-control study investigated 1150 patients from the cohort of all patients with a diagnosis of SI-NETs in Sweden between 1961 and 2001. The study cases consisted of all patients who died of SI-NETs during the study period. Each case was assigned a control subject matched by age at diagnosis and calendar period. Possible prognostic factors [gender, degree of symptoms, indication for surgery, World Health Organization (WHO) stage] were evaluated in uni- and multivariable analyses. RESULTS: The patients with symptomatic disease had an increased risk of dying. The indication for primary surgery influenced survival, showing a more negative prognosis for elective surgery. The WHO stage influenced survival, and stage 4 patients had an almost threefold risk of dying compared with stages 1 to 3b patients. CONCLUSIONS: This study showed that preoperative symptoms are important in prognostication for SI-NETs. Hormonal symptoms generally signify a patient with a more advanced disease stage and a worse prognosis. Including symptomatic disease together with the WHO stage and grade could possibly increase the accuracy of prognostication.

Octreotide long-acting repeatable use among elderly patients with carcinoid syndrome and survival outcomes: a population-based analysis.

BACKGROUND: Octreotide long-acting repeatable (LAR) is indicated for the treatment of carcinoid syndrome and diarrhea related to VIPoma, and may delay tumor growth in patients with neuroendocrine tumors (NETs). To the authors' knowledge, the pattern of octreotide LAR use in clinical practice and its impact on survival outcomes has not been well documented. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, the authors identified patients with NET aged ≥ 65 years who were diagnosed between July 1999 and December 2007. Patients with US Food and Drug Administration-approved indications for octreotide LAR were identified from Medicare claims. Multivariate logistic regression was performed to ascertain factors associated with octreotide LAR use, whereas the Cox proportional hazards model was used to evaluate the impact of octreotide LAR on survival. RESULTS: Among those with Food and Drug Administration-approved indications, 245 of 4848 patients with distant-stage disease (51%) and 81 of 807 patients with local/regional disease (10%) initiated treatment with octreotide LAR within 6 months of diagnosis. Multivariate logistic regression indicated that among those with distant-stage disease, older age (≥ 80 years vs 65-69 years) (odds ratio [OR], 0.43; 95% confidence interval [95% CI], 0.23-0.81), female sex (OR, 0.62; 95% CI, 0.40-0.97), and living in the South (vs Northeast) (OR, 0.36; 95% CI, 0.18-0.72) were associated with a lower likelihood of using octreotide LAR. The multivariate proportional hazards model showed that octreotide LAR provided a significant 5-year survival benefit for patients with distant-stage disease (hazards ratio, 0.61; P ≤ .001), whereas this survival benefit was not shown for the patients with local/regional stage (hazards ratio, 0.88; P = .563). CONCLUSIONS: The results of this retrospective study suggest a possible survival benefit for the use of octreotide LAR in elderly patients with distant-stage NET with carcinoid syndrome. The results of the current study also suggest that octreotide LAR is underused in this population despite recommended guidelines.

[Surgical treatment of pulmonary carcinoids - ten-year results]. / Chirurgische Behandlung von Lungenkarzinoiden - Zehnjahresergebnisse.

INTRODUCTION: Carcinoids are malignant neuro-endocrine tumours occurring in the bronchopulmonary location in about 25 %, and accounting for approximately 2 % of all pulmonary tumours. MATERIAL AND METHODS: Our retrospective analysis included 27  patients, 14  men and 13  women, mean age 58.4  years, treated from 2000 to 2009 for carcinoids in bronchopulmonary locations. The tumour manifested clinically in 52 % of the cases, the most common symptom being cough; one tumour manifested as carcinoid syndrome. All patients underwent fibrobronchoscopy that was positive in 20  cases (74.1 %). Pre-surgery histological diagnoses were made in 13  patients (48.1 %). Chest CT scans were carried out in 26  patients, and the investigation failed to detect the expected pathological process in 2  of the patients. Octreoscans were carried out in 12  patients, and were successful in identifying a primary neuroendocrine tumour in 75 %. RESULTS: All patients in the sample underwent rad-ical surgical therapy; the most common surgical procedure was lobectomy (70.4 %). Perioperative morbidity and mortality were zero. Typical carcinoids were found in 20  cases while 7  cases were atypical carcinoids, 20  tumours were located centrally. 74 % of the tumours were consistent with stage  I A disease. Mean follow-up period was 47 (range: 6-134)  months. Local recurrences were observed in 2  patients (7.4 %), but the tumour disseminated in 4  patients (14.8 %). Two patients (7.4 %) died during the follow-up period. Overall five-year survival in the sample was 92.3 %, 90.9 % in the typical carcinoid group and 100 % for atypical carcinoids. We found a statistically significant association between disease-free interval and histological type of the tumour; the risk of progression was 8  times higher in -patients with atypical carcinoids compared to patients with typical carcinoids (Log-Rank-Test: p-value = 0.0049). CONCLUSION: Radical surgical treatment of bronchopulmonary carcinoids is the optimum therapeutic approach that results in the best results both regarding perioperative morbidity and mortality and regarding long-term survival of the patients.

Octreotide long-acting repeatable among elderly patients with neuroendocrine tumors: a survival analysis of SEER-Medicare data.

BACKGROUND: Octreotide long-acting repeatable (LAR) is approved in the United States for the management of carcinoid syndromes among patients with neuroendocrine tumors (NET). The objective of our study is to evaluate the impact of octreotide LAR on overall survival (OS), as it has not been established. METHODS: NET patients of 65 years and older diagnosed between January 1999 and December 2009 were identified from the SEER-Medicare database. We compared the OS of NET patients who started octreotide LAR within 12 months of diagnosis with those who did not receive it during the same period. We conducted Kaplan-Meier estimations and Cox proportional hazard models to examine the association between octreotide LAR and OS. RESULTS: Among 1,176 distant stage patients, 233 (20%) received octreotide LAR within 12 months of diagnosis, compared with 2% (96 in 5,764) of local/regional stage patients. Median OS for patients who started octreotide LAR within 12 months was 35.22 months [95% confidence interval (CI), 27.96-47.77], longer than those who did not receive it (19.15 months; 95% CI, 16.36-22.80; P < 0.0001). Multivariate analysis showed that octreotide LAR was associated with significant survival improvement for distant stage patients (HR, 0.68; P < 0.001) and in the subgroups with (HR, 0.65; P, 0.003) and without (HR, 0.55; P, 0.002) carcinoid syndrome. No survival benefit was found among local/regional stage patients. CONCLUSION: This population-based study suggests potential survival benefits of octreotide LAR among elderly distant stage NET patients, both with or without carcinoid syndrome. IMPACT: The study provides population-based evidence of a positive association between octreotide LAR and overall survival among elderly distant stage NET patients.

Octreotide and interferon alfa: a new combination for the treatment of malignant carcinoid tumours.

24 patients with malignant carcinoid tumours received octreotide and interferon alfa (IFN-alpha). All the patients initially received octreotide 50-100 micrograms, twice daily. When progressive symptoms or increasing biochemical markers were observed, the daily dose was raised to a median 300 micrograms. If the initial dose proved ineffective or if no improvement was seen after escalation, IFN-alpha was added (median 9 MU subcutaneously per week). After the addition of IFN-alpha, 17 of the 22 patients (77%) with elevated urinary 5-hydroxyindoleacetic acid showed a significant (> 50%) reduction. Only 1 patient progressed and 4 had continuously stable biochemical disease. No significant reduction in tumour size was noted; in 5 patients, the tumour continued to grow despite decreasing hormone levels. 18 patients had carcinoid syndrome when IFN-alpha was added in 10 (56%) symptoms ameliorated. Thus, the addition of IFN-alpha is beneficial for patients with malignant carcinoid tumours that progress and/or who do not respond to octreotide.

The carcinoid syndrome: comparison of 21 necropsy subjects with carcinoid heart disease to 15 necropsy subjects without carcinoid heart disease.

Carcinoid heart disease is a morphologically specific type of cardiac disorder that involves the mural and valvular endocardium on the right side of the heart. Twenty-one subjects (57 percent) (Group I) with carcinoid heart disease and 15 subjects (43 percent) (Group II) without carcinoid heart disease were studied at necropsy. The two groups were similar in mean age (54 years versus 55 years), duration of clinical illness (4.7 years versus 6.3 years), body weight (50 kg versus 52 kg), systemic blood pressure (117/77 mm Hg versus 128/77 mm Hg), blood hematocrit levels (37 percent versus 36 percent), total serum protein levels (6.0 g/dl), and serum albumin levels (2.2 g/dl versus 2.6 g/dl). The two groups were different in the frequency of the presence of precordial murmurs consistent with tricuspid regurgitation and/or pulmonic stenosis (95 percent versus 13 percent), cardiomegaly by chest radiography (38 percent versus 0), low voltage on electrocardiography (47 percent versus 0), and location of the primary site of the carcinoid tumor. Total electrocardiographic 12-lead QRS voltage was similar in each group (105 mm versus 132 mm) (10 mm = 1 mV). Of Group I subjects, 43 percent died of cardiac causes; none of the Group II subjects died of cardiac causes. Of the 21 subjects with carcinoid heart disease, seven had left-sided cardiac involvement, but in none was it of functional significance. Thus, although carcinoid heart disease frequently is the cause of death in patients with the carcinoid syndrome, the development of carcinoid heart disease is not related to the duration of symptoms of the carcinoid syndrome.

Clinical and echocardiographic comparison of patients with the carcinoid syndrome with and without carcinoid heart disease.

To correlate clinical and laboratory variables in carcinoid heart disease, clinical data, echocardiograms, 24-hour urinary 5-hydroxyindoleacetic acid levels and liver function tests were evaluated in 30 patients with the carcinoid syndrome. The dominant cardiac lesion of carcinoid heart disease by echocardiography and Doppler was severe tricuspid regurgitation with right ventricular volume overload. A characteristic finding was thickened, retracted tricuspid valve leaflets that were fixed in a partially open position. Carcinoid heart disease was progressive and often fatal. The 17 patients with echocardiographic evidence of carcinoid heart disease had higher peak levels of urinary 5-hydroxyindoleacetic acid (331 +/- 231 vs 58 +/- 78 mg, p less than 0.001) and more severe hepatic dysfunction than the 13 patients without carcinoid heart disease. Although duration of symptoms of the carcinoid syndrome before echocardiography was similar for patients with and without carcinoid heart disease (5.4 +/- 6.4 vs 6.2 +/- 5.9 years, respectively, p greater than 0.1), survival after echocardiography was shorter for those with carcinoid heart disease (1.9 +/- 1.4 vs 3.8 +/- 2.9 years, p = 0.05). The findings support the concept that long-term exposure of the endocardium to serotonin in the right side of the heart leads to the development of heart lesions; in addition, progressive hepatic dysfunction may allow more serotonin to bypass liver enzymes and reach the right side of the heart.

Gastroenteropancreatic endocrine tumors: effect of Sandostatin on tumor growth. The German Sandostatin Study Group.

One hundred fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumors entered a prospective multicenter trial (12 patients with gastrinoma, 53 with carcinoid syndrome, 45 with nonfunctioning tumors, and five with other endocrine GEP tumors) to determine the efficacy of 200 micrograms Sandostatin three times a day in the control of tumor growth. This interim report describes the results in 85 patients. Thirty-four patients died, 14 before and 20 after the first follow-up investigation, indicating a "negative" selection of patients included in the trial and suggesting that Sandostatin cannot prevent disease progress when it is far advanced. In the evaluation of 68 patients monitored for at least 3 months, partial regression was observed in 4.4%, stable disease in 50%, and tumor progression in 45%. However, an initially favorable response frequently occurred with a decrease in response later: 54.4% at 3 months to 38% at 12 months for the whole group of patients. Proven inhibition of tumor growth was mirrored by suppression of serum and urine hormone parameters. It is concluded that Sandostatin exerts a beneficial effect on tumor growth in patients with metastatic endocrine GEP tumors. This beneficial effect decreases with time and is as yet unpredictable in the individual patient.

Tryptophan in the treatment of carcinoid crisis.

A 56-year-old woman was admitted with carcinoid crisis and became comatose. Blood tryptophan at this stage was 5 micrograms/ml; after treatment with 3.4 g tryptophan daily her level of consciousness improved and blood tryptophan increased to 10 micrograms/ml. The carcinoid syndrome was not exacerbated by tryptophan. Tryptophan may have a supportive role in the management of carcinoid crisis.

Duodenal carcinoid tumors: how aggressive should we be?

Duodenal carcinoid tumors are uncommon. It is not known whether they behave more like carcinoid tumors in the appendix (indolent course) or those in the ileum (often virulent)-crucial information for determining the need for radical resection. A retrospective review at our tertiary referral center (from 1976 to 1999) identified 27 patients with primary duodenal carcinoid lesions, excluding functional islet cell tumors. Endoscopic biopsy provided the diagnosis in 78% of patients. Treatment was by endoscopic excision (n = 11), transduodenal excision (n = 8), pancreaticoduodenectomy (n = 3), segmental distal duodenectomy (n = 2), or palliative operation (n = 2). One patient did not undergo operation because of comorbidity. Eighteen of 19 patients with tumors smaller than 2 cm remained disease free after local (endoscopic or transduodenal) excision. The exception was a patient with a small periampullary carcinoid lesion. In contrast, all four patients with carcinoid tumors 2 cm or larger who were resected for cure developed a recurrence (2 to 9 years postoperatively). We conclude that duodenal carcinoid tumors smaller than 2 cm may be excised locally; to ensure complete resection we recommend open transduodenal excision for tumors between 1 and 2 cm. Endoscopic follow-up is indicated. It is unclear whether patients with larger tumors benefit from more aggressive locoregional resection. Ampullary/periampullary carcinoid tumors should be considered separately, as their behavior is unpredictable.

Carcinoids and the carcinoid syndrome.

The many manifestations of carcinoids will continue to puzzle and intrigue surgeons. Because these are dynamic tumors which produce multiple hormones with many potential side effects, an aggressive surgical debulking of them is advocated. Even in the presence of metastatic disease, some long-term survival can be anticipated. The most debillitating aspect of this tumor to the patient is the carcinoid syndrome. The symptoms occur erratically and are often not well controlled by presently available medication. Although metastatic disease present at diagnosis is most commonly seen with jejunoileal carcinoids, colorectal carcinoids appear to be the most lethal tumors. However, they are rarely associated with the symptoms of carcinoid syndrome. Carcinoids may often be associated with other types of tumors, some of which are known to produce their own hormones. Survival of the patients seems to be related to their other tumor type rather than the primary carcinoid. The clinician should be aware of the strong association of carcinoids with peptic ulcer disease. The ulcer diathesis is probably related to ectopic histamine production and can usually be controlled by cimetidine and antacids, although surgical intervention may be required.

Gastrointestinal carcinoid tumors.

Fifty-five patients were evaluated and treated for gastrointestinal (GI) carcinoid tumors at our institution from 1968 through 1988. Thirty patients had primary tumors smaller than 1 cm and were treated surgically or endoscopically by local excision, whereas 25 underwent resection with regional lymphadenectomy for larger primaries. At the time of initial treatment 17 patients demonstrated metastasis. Although 13 of these patients had primary tumors larger than 2 cm, in four patients with ileal carcinoids, the primary measured 0.8 to 1.5 cm. Serosal involvement was present in nine of 17 patients with metastasis. With a follow-up range of 3 months to 20 years, six patients have died with metastatic carcinoid tumor, two patients died without evidence of disease, 12 patients are alive with metastasis, and 35 patients are alive, free of disease. In this series three determinants for risk of metastasis in GI carcinoid tumors were evident: primary size, serosal penetration, and primary site in the small intestine. In patients with any of these risk factors, resection with regional lymphadenectomy is recommended.

Carcinoid syndrome: a statistical evaluation of 748 reported cases.

No statistical evaluation of patients with carcinoid syndrome in a reliable number of cases has been available in the past 35 years. To update our knowledge about the syndrome, we have evaluated from various clinicopathologic viewpoints a large series of patients with the syndrome reported up to date. The data of 748 patients with the syndrome were collected from 8876 carcinoid patients reported in the literature and analyzed by the Gut-Pancreatic Endocrinoma Analyzing System (the Niigata Registry). The results are summarized as follows. 1) The patients with the syndrome had a tendency to be older than those without it. 2) The incidence of the syndrome was 8.4% of 8876 carcinoid patients. 3) Serotonin activities were extremely high in patients with the syndrome as compared to those without it (91.7% versus 26.6%). 4) The rate of metastases was higher in patients with the syndrome than in those without it (84.8% versus 29.2%), and higher in the liver than in lymph nodes among patients with the syndrome (73.4% versus 37.4%). 5) Flushing and carcinoid heart as most specific clinical manifestations of the syndrome were recorded at 78.3% and 17.4%, respectively. 6) The 5-year survival rate after resection of primary lesions was 76.0% of 304 patients with the syndrome, lower in patients with digestive carcinoids than in those with extradigestive lesions (67.2% versus 88.7%). It is expected that the results obtained in the present evaluation on patients with carcinoid syndrome will provide investigators active in this specialized field with useful and extensive information for their future activities.

Atypical bronchial carcinoids. Review of 46 patients.

BACKGROUND: The purpose of this study was to assess the behaviour of atypical carcinoids operated at our Department in the period 1977-1998 and to review the last 19 cases according to Capella's classification (1994), indicating the most adequate surgical approach. METHODS: On the basis of anatomo-pathological characteristics, we have reviewed surgical treatment and outcome in 46 patients, submitted in the last 22 years to surgical resection for neuroendocrine neoplasms. RESULTS: 5-year survival is 77.2%; 10-year survival is 53.2%. Lymph node metastases are also important for survival, but less than the histotype. The review of our last six years' series, according to Capella's classification, of 19 patients affected by so-called atypical carcinoids revealed that: 5 were well differentiated neuroendocrine tumors (WDNT), 12 were well differentiated neuroendocrine carcinomas (WDNC), 2 were small cell neuroendocrine carcinomas (SCLC). The 5-year overall survival of our cases is 78%, for the WDNT 100%, for WDNC 81.2%. Of the 2 patients with SCLC, one survived 2 months; the other is still alive 5 months after surgery. CONCLUSIONS: The authors conclude that 5-year and 10-year survival are strongly related to the histological type of neuroendocrine neoplasm and to the presence of lymph node metastases. Capella's anatomo-pathological classification helps to give a more accurate prognosis for survival in so-called "atypical carcinoids". If the neoplasm is malignant, the authors recommend radical resection, if possible.

[Management of digestive system carcinoid tumors and carcinoid syndrome]. / Manejo del tumor carcinoide del aparato digestivo y del síndrome carcinoide.

INTRODUCTION: Carcinoid tumors are rare, most of the publications are case reports and the clinical series are uncommon. The quality of life and survival time of these patients depend on the adequate control of tumor growth and good palliation of their symptoms. AIMS: The purpose of this study is to inform epidemiological data and forms of management for these tumors and the Carcinoid Syndrome at the National Institute of Cancerology (INCan) at Mexico City in the last 15 years. METHODS: A retrospective review of the clinical records of patients diagnosed and treated at the INCan with carcinoid tumors from 1982 to 1997 was performed. RESULTS: The most common origin place was the gastrointestinal tract (GI), and the majority involved the right colon and the appendix. The longest survivors were patients with tumors originated in the appendix, tumors smaller than 2 cm or localized. At the time of diagnosis 47% of patients had metastatic disease that was also a poor prognostic factor. The experience in our hospital seem to support the use of interferon alone or in combination with octreotide or debulking surgery for the palliation of carcinoid syndrome. CONCLUSIONS: Carcinoid tumors are rare, and have a slow growth and less aggressive biological nature than noncarcinoid tumors. Treatment should be focused on trying to cure the small or localized lesions or to find the best palliative method for those symptomatic advanced lesions.

Comparison of prognostic value of tissue Doppler imaging in carcinoid heart disease versus the value in patients with the carcinoid syndrome but without carcinoid heart disease.

The aim of this study was to evaluate the prognostic value of tissue Doppler imaging (TDI) in carcinoid heart disease (CHD). We prospectively enrolled 56 consecutive patients with proved digestive endocrine tumor and carcinoid syndrome. All patients underwent serial conventional, contrast, and TDI echocardiographic studies. The end point was all-cause mortality. Mean follow-up was 34 +/- 21 months. At the end of follow-up, 30 patients (54%) presented right CHD and 13 patients (23%) left CHD. A progression of CHD was documented in 23 patients (41%). Twenty-two patients (39%) died during follow-up. According to mortality receiver operating characteristic curves, ratio of early transmitral flow velocity to early diastolic mitral annulus velocity (E/e' ratio) associated with an optimal sensitivity of 80% and specificity of 90% was 8. Mortality rate was significantly higher when the E/e' ratio was >or=8 (94% vs 10% when E/e' ratio was <8, p <0.0001). Using univariate analysis, the following factors were associated with death: left-sided CHD (p = 0.07) and E/e' ratio >or=8 (p <0.0001). The only independent marker of death detected by multivariate analysis was an E/e' ratio >or=8 (odds ratio 6.2, 95% confidence interval 1.95 to 19.7, p = 0.002). In conclusion, TDI used during routine transthoracic echocardiography can be helpful to identify high-risk patients with CHD.