Should We Abandon Systematic Pelvic and Paraaortic Lymphadenectomy in Low-Grade Serous Ovarian Cancer?

BACKGROUND: Low-grade serous ovarian carcinoma (LGSOC) is a rare disease that accounts for 5% of all ovarian cancers and requires surgical complete debulking. To date, the prognostic value of pelvic and paraaortic lymphadenectomy remains unclear in this population. PATIENTS AND METHODS: This retrospective cohort of patients with a diagnosis of LGSOC was registered in the Tumeurs Malignes Rares Gynécologiques national network, between January 2000 and July 2017, at 25 centers. All LGSOC were confirmed after pathological review and operated by primary debulking surgery (PDS) or interval debulking surgery after neoadjuvant chemotherapy (NACT-IDS). Primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 126 patients were included, 86.1% were stage III/IV, and 74.6% underwent lymph node dissection (LND). According to the Completeness of Cancer Resection (CCR) score, 83.7% had complete resection. Median OS was 130 months, and median PFS was 41 months. Pelvic and paraaortic LND had no significant impact on OS (p = 0.78) or DFS (p = 0.93), and this was confirmed in subgroups (advanced stages FIGO III/IV, CCR score 0/1 or 2/3, and timing of surgery PDS or NACT-IDS). Histological positive paraaortic lymph nodes had a significant negative impact on PFS in the whole population (HR 2.21, 1.18-4.39, p = 0.02) and in the CC0/CC1 population (HR, 2.28, 1.13-4.59, p = 0.02). CONCLUSIONS: Systematic pelvic and paraaortic LND in patients with LGSOC improved neither overall nor PFS. A prospective trial would be necessary to validate these results but would be difficult to conduct due to the rarity of this disease.

Need for risk-adapted therapy for malignant ovarian germ cell tumors: A large multicenter analysis of germ cell tumors' patients from French TMRG network.

BACKGROUND: Malignant ovarian germ cell tumors are rare tumors, affecting young women with a generally favorable prognosis. The French reference network for Rare Malignant Gynecological Tumors (TMRG) aims to improve their management. The purpose of this study is to report clinicopathological features and long-term outcomes, to explore prognostic parameters and to help in considering adjuvant strategy for stage I patients. PATIENTS AND METHODS: Data from patients with MOGCT registered among 13 of the largest centers of the TMRG network were analyzed. We report clinicopathological features, estimated 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) of MOGCT patients. RESULTS: We collected data from 147 patients including 101 (68.7%) FIGO stage I patients. Histology identifies 40 dysgerminomas, 52 immature teratomas, 32 yolk sac tumors, 2 choriocarcinomas and 21 mixed tumors. Surgery was performed in 140 (95.2%) patients and 106 (72.1%) received first line chemotherapy. Twenty-two stage I patients did not receive chemotherapy. Relapse occurred in 24 patients: 13 were exclusively treated with upfront surgery and 11 received surgery and chemotherapy. 5y-EFS was 82% and 5y-OS was 92.4%. Stage I patients who underwent surgery alone had an estimated 5y-EFS of 54.6% and patients receiving adjuvant chemotherapy 94.4% (P < .001). However, no impact on estimated 5y-OS was observed: 96.3% versus 97.8% respectively (P = .62). FIGO stage, complete primary surgery and post-operative alpha fetoprotein level significantly correlated with survival. CONCLUSION: Adjuvant chemotherapy does not seem to improve survival in stage I patients. Active surveillance can be proposed for selected patients with a complete surgical staging.

The OncoSim model: development and use for better decision-making in Canadian cancer control.

The Canadian Partnership Against Cancer was created in 2007 by the federal government to accelerate cancer control across Canada. Its OncoSim microsimulation model platform, which consists of a suite of specific cancer models, was conceived as a tool to augment conventional resources for population-level policy- and decision-making. The Canadian Partnership Against Cancer manages the OncoSim program, with funding from Health Canada and model development by Statistics Canada. Microsimulation modelling allows for the detailed capture of population heterogeneity and health and demographic history over time. Extensive data from multiple Canadian sources were used as inputs or to validate the model. OncoSim has been validated through expert consultation; assessments of face validity, internal validity, and external validity; and model fit against observed data. The platform comprises three in-depth cancer models (lung, colorectal, cervical), with another in-depth model (breast) and a generalized model (25 cancers) being in development. Unique among models of its class, OncoSim is available online for public sector use free of charge. Users can customize input values and output display, and extensive user support is provided. OncoSim has been used to support decision-making at the national and jurisdictional levels. Although simulation studies are generally not included in hierarchies of evidence, they are integral to informing cancer control policy when clinical studies are not feasible. OncoSim can evaluate complex intervention scenarios for multiple cancers. Canadian decision-makers thus have a powerful tool to assess the costs, benefits, cost-effectiveness, and budgetary effects of cancer control interventions when faced with difficult choices for improvements in population health and resource allocation.

Using the Cancer Risk Management Model to evaluate the health and economic impacts of cytology compared with human papillomavirus DNA testing for primary cervical cancer screening in Canada.

BACKGROUND: In Canada, discussion about changing from cytology to human papillomavirus (hpv) dna testing for primary screening in cervical cancer is ongoing. However, the Canadian Task Force on Preventive Health Care has not yet made a recommendation, concluding that the evidence is insufficient. METHODS: We used the cervical cancer and hpv transmission models of the Cancer Risk Management Model to study the health and economic outcomes of primary cytology compared with hpv dna testing in 14 screening scenarios with varying screening modalities and intervals. Projected cervical cancer cases, deaths, colposcopies, screens, costs, and incremental cost-effectiveness were evaluated. We performed sensitivity analyses for hpv dna test costs. RESULTS: Compared with triennial cytology from age 25, 5-yearly hpv dna screening alone from age 30 resulted in equivalent incident cases and deaths, but 55% (82,000) fewer colposcopies and 43% (1,195,000) fewer screens. At hpv dna screening intervals of 3 years, whether alone or in an age-based sequence with cytology, screening costs are greater, but at intervals of more than 5 years, they are lower. Scenarios on the cost-effectiveness frontier were hpv dna testing alone every 10, 7.5, 5, or 3 years, and triennial cytology starting at age 21 or 25 when combined with hpv dna testing every 3 years. CONCLUSIONS: Changing from cytology to hpv dna testing as the primary screening test for cervical cancer would be an acceptable strategy in Canada with respect to incidence, mortality, screening and diagnostic test volumes.

Using the Cancer Risk Management Model to evaluate colorectal cancer screening options for Canada.

BACKGROUND: Several screening methods for colorectal cancer (crc) are available, and some have been shown by randomized trials to be effective. In the present study, we used a well-developed population health simulation model to compare the risks and benefits of a variety of screening scenarios. Tests considered were the fecal occult blood test (fobt), the fecal immunochemical test (fit), flexible sigmoidoscopy, and colonoscopy. Outcomes considered included years of life gained, crc cases and deaths prevented, and direct health system costs. METHODS: A natural history model of crc was implemented and calibrated to specified targets within the framework of the Cancer Risk Management Model (crmm) from the Canadian Partnership Against Cancer. The crmm-crc permits users to enter their own parameter values or to use program-specified base values. For each of 23 screening scenarios, we used the crmm-crc to run 10 million replicate simulations. RESULTS: Using base parameter values and some user-specified values in the crmm-crc, and comparing our screening scenarios with no screening, all screening scenarios were found to reduce the incidence of and mortality from crc. The fobt was the least effective test; it was not associated with lower net cost. Colonoscopy screening was the most effective test; it had net costs comparable to those for several other strategies considered, but required more than 3 times the colonoscopy resources needed by other approaches. After colonoscopy, strategies based on the fit were predicted to be the most effective. In sensitivity analyses performed for the fobt and fit screening strategies, fobt parameter values associated with high-sensitivity formulations were associated with a substantial increase in test effectiveness. The fit was more cost-effective at the 50 ng/mL threshold than at the 100 ng/mL threshold. CONCLUSIONS: The crmm-crc provides a sophisticated and flexible environment in which to evaluate crc control options. All screening scenarios considered in this study effectively reduced crc mortality, although sensitivity analyses demonstrated some uncertainty in the magnitude of the improvements. Where possible, local data should be used to reduce uncertainty in the parameters.

[Benefit-risk balance of hormone replacement therapy: Cancers and mortality. Postmenopausal women management - CNGOF and GEMVi clinical practice guidelines]. / La balance bénéfice­risque du traitement hormonal de la ménopause : cancers et mortalité. RPC Les femmes ménopausées CNGOF ­ GEMVi.

The use of hormone replacement therapy (HRT) for menopausal women has been the subject of much controversy in recent years, particularly concerning the carcinologic risks. The purpose of this review is to evaluate the impact of the use of HRT on the risk of gynecological but also extra-gynecological cancers. The effect of the type and the duration of use of HRT in menopausal women will also be discussed. The beneficial impact of HRT on overall mortality is also an element that will be discussed and must be taken into account when evaluating the benefit-risk balance of HRT for menopausal women.

[Virilizing ovarian tumors in the menopausal patient]. / Tumeurs virilisantes de l'ovaire chez la femme ménopausée.

Virilizing ovarian tumors are rare and can occur at any age. In postmenopausal women, they commonly present with signs of masculinization. These tumors should be suspected in any patient with virilization and high testosterone levels (>1ng/mL). Tumor localization is sometimes difficult. These tumors are usually benign; surgical resection is the accepted treatment. Masculinizing consequences of hormonal secretions may be managed by cosmetologic treatments which should not be overlooked.

Characterization of a novel capsaicin/heat ongoing pain model.

BACKGROUND: Human experimental pain models provide an important translational link between pre-clinical models and clinical pain. Using topical capsaicin and continuous heat application, the novel capsaicin/heat ongoing pain (CHOP) model induces long-lasting experimental pain of which the perceived intensity can be individually adjusted. METHODS: In the CHOP model, capsaicin or control cream is applied to a 10 × 10 cm skin area and a heating pad is applied over the area after cream removal. Two experiments in healthy participants were performed for model characterization. In Experiment 1, a constant temperature was applied for 60 min; in Experiment 2, temperature was adjusted to maintain a constant perceived intensity for 60 min. RESULTS: Experiment 1: across participants, constant temperature induced initial habituation followed by an increase in sensation back to baseline. Cluster analysis revealed that half the participants sensitized to the constant temperature, while the other half did not. The degree of sensitization was related to the baseline pain unpleasantness, relative to pain intensity. Experiment 2: constant perceived intensity was achieved in the painful and a non-painful control condition. The two conditions did not differ regarding possibly confounding variables, including blood pressure, heart rate, inflammation or physiological stress as measured by surrogate markers. Secondary allodynia and hyperalgesia were reported more following painful compared to control stimulation. Sensitizers as determined in Experiment 1 were also more pain sensitive in Experiment 2. CONCLUSION: The CHOP model reproduces some aspects of clinical pain, such as longer duration, sensitization, secondary allodynia and hyperalgesia. SIGNIFICANCE: Here we demonstrate a novel pain model that can be applied for up to an hour without tissue damage. The CHOP model allows for investigation of primary and secondary hyperalgesia as well as top-down influences on sensitization, thereby providing an experimental model that can be used to assess clinically-oriented questions.

A cloned fragment of HeLa DNA containing consensus sequences of satellite II and III DNA hybridizes with the Drosophila P-element and with the 1.8 kb family of human KpnI fragments.

We have cloned a repetitive EcoRI fragment from the human genome which displays weak homologies with the Drosophila melanogaster transposable P-element. This cloned DNA appeared not to be a mobile element but, instead, a divergent member of human satellite II or III DNAs. We present here the first complete nucleotide sequence of a 1.797 kilobase pair (kb) satellite-like DNA. Moreover, this EcoRI satellite monomer contains a unique sequence of 49 basepairs (bp) that is devoid of the satellite consensus repeat 5'TTCCA3'. Southern hybridization analysis revealed that the cloned insert is closely related to a highly repetitive 1.8 kb KpnI family of tandemly organized satellite DNAs. Thus, the relationships among these satellite DNA families appear to be complex and may be a factor in their copy number, position and spatial organization.

Effect of amlodipine, atenolol and their combination on myocardial ischemia during treadmill exercise and ambulatory monitoring. Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS) Investigators.

OBJECTIVES: This study compared the effects of amlodipine, atenolol and their combination on ischemia during treadmill testing and 48-h ambulatory monitoring. BACKGROUND: It is not known whether anti-ischemic drugs exert similar effects on ischemia during ambulatory monitoring and exercise treadmill testing. METHODS: Patients with stable coronary artery disease and ischemia during treadmill testing and ambulatory monitoring were randomized to receive amlodipine (n = 51) or atenolol (n = 49). Each group underwent a counterbalanced, crossover evaluation of single drug and placebo, followed by evaluation of the combination. RESULTS: Amlodipine and the combination prolonged exercise time to 0.1-mV ST segment depression by 29% and 34%, respectively (p < 0.001) versus 3% for atenolol (p = NS). During ambulatory monitoring, the frequency of ischemic episodes decreased by 28% with amlodipine (p = 0.083 [NS]), by 57% with atenolol (p < 0.001) and by 72% with the combination (p < 0.05 vs. both single drugs; p < 0.001 vs. placebo). Suppression of ischemia during exercise testing and ambulatory monitoring was similar in patients with and without exercise-induced angina. Exercise time to angina improved by 29% with amlodipine (p < 0.01), by 16% with atenolol (p < 0.05) and by 39% with the combination (p < 0.005 vs. placebo, atenolol and amlodipine). In patients with angina, total exercise time improved by 16% with amlodipine (p < 0.001), by 4% with atenolol (p = NS) and by 19% with the combination (p < 0.05 vs. placebo and either single drug). In those patients without angina, no therapy significantly improved total exercise time. CONCLUSIONS: Ischemia during treadmill testing was more effectively suppressed by amlodipine, whereas ischemia during ambulatory monitoring was more effectively suppressed by atenolol. The combination was more effective than either single drug in both settings.

Enalapril versus digoxin in patients with congestive heart failure: a multicenter study. Canadian Enalapril Versus Digoxin Study Group.

Patients with New York Heart Association functional class II or III heart failure stabilized on furosemide therapy were entered into a randomized controlled trial comparing enalapril (n = 72) and digoxin (n = 73). End points were clinical outcome, treadmill exercise capacity and echocardiographic left ventricular dimensions. Improvement in clinical outcome was defined as a reduction of at least one functional class or withdrawal because of an adverse clinical event. After 4 weeks, 13 patients receiving enalapril showed improvement, 55 had no change and 9 manifested deterioration compared with 7, 49 and 17, respectively, in the digoxin group (p less than 0.01). After 14 weeks, 13 patients receiving enalapril showed improvement, 50 had no change and 9 manifested deterioration, compared with 14, 37 and 22, respectively, in the digoxin group (p less than 0.025). More patients in the digoxin group were withdrawn because of an adverse clinical event (p less than 0.05). Exercise time and percent fractional shortening improved in both groups (p less than 0.001 and less than 0.05, respectively), with no significant difference between groups (p greater than 0.50). Both rate-pressure product and subjectively evaluated exertion during submaximal exercise were reduced only in the enalapril group. Although the majority of patients in both groups did well, those receiving enalapril experienced fewer adverse clinical events and had less fatigue during submaximal exercise.

Relative importance of psychologic traits and severity of ischemia in causing angina during treadmill exercise. Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS) Investigators.

OBJECTIVES: This study was conducted to compare the influence of psychologic traits versus ischemia severity on the occurrence of angina during treadmill exercise. BACKGROUND: Some studies suggest that angina is associated with certain psychologic traits, whereas others show an association with more severe ischemia. The relative influence of these two factors and the extent to which they interact are not known. METHODS: Off-drug treadmill exercise testing and a battery of psychologic tests were performed on 122 patients with known coronary artery disease. Psychologic tests measured sensitivity to physical symptoms, denial and deception, type A behavior, anger, hostility, depression, marital adjustment and amount of external stress. Stepwise logistic regression was used to determine the independent association of psychologic traits, ischemic threshold and exercise tolerance with the occurrence of angina. RESULTS: Angina during treadmill exercise was reported by 66 of 122 patients. On univariate testing, angina was positively associated with sensitivity to physical symptoms (p < 0.001), type A behavior (p = 0.021) and depression (p = 0.032) and was negatively associated with exercise tolerance (p < 0.001) and work load threshold for ischemia (p < 0.01). Multivariate analysis revealed independent and additive associations of angina with sensitivity to physical symptoms (p = 0.003), exercise capacity (p = 0.003) and work load threshold for ischemia (p = 0.018). Once these were included in a logistic model, depression and type A behavior were no longer significant. Other psychologic traits showed no association with angina. CONCLUSIONS: Sensitivity to physical symptoms, ischemic threshold and exercise tolerance are independently associated with angina, with sensitivity to physical symptoms having the stronger influence. The physiologic and psychologic mechanisms underlying symptom perception have an influence on angina that is independent of and additive to the severity of underlying ischemia.

Impact of diabetes on crash risks of truck-permit holders and commercial drivers.

OBJECTIVE: The U.S. and some Canadian government agencies have waived commercial license restrictions for some insulin-using diabetic drivers. However, the U.S. Federal Highway Administration is no longer giving waivers. Scientific evidence to support such regulations has been sparse. This article presents detailed analyses of crash risks for users and nonusers of insulin among diabetic truck-permit holders in Québec, Canada. RESEARCH DESIGN AND METHODS: Diabetic truck-permit holders were group-matched by age to a random sample of healthy permit holders. Data on permits, medical conditions, and crashes involving 13,453 permit holder-years in 1987-1990 were extracted from the files of the public insurer for automobile injuries in Québec. Additional health status data were obtained from the provincial public health insurer. A telephone survey was conducted to collect data on driving patterns and exposure. Risk ratios were estimated using negative binomial regression models. RESULTS: Risk ratios for crashes vary by category of diabetes. Permit holders for single-unit trucks (STs) who are diabetic without complications and not using insulin have an increased crash risk of 1.68 when compared with healthy permit holders of the same permit class. When controlling for risk exposure, commercial drivers with an ST permit and the same diabetic condition have an increased risk of 1.76. Insulin use is not associated with higher crash risk. CONCLUSIONS: The increased crash risk for the group with uncomplicated diabetes not using insulin is a new finding. The lack of consistent increases in crash risks among diabetic commercial drivers with complications or who use insulin may be a "healthy worker effect" masking the real risk, because these licensees have a lower participation rate as professional drivers.

[Exploring a non-inflammatory clinical breast mass: Clinical practice guidelines]. / Exploration d'un syndrome de masse clinique non inflammatoire du sein: recommandations pour la pratique clinique.

PURPOSE: The aim of the study was to assess the diagnostic value of physical examination, radiologic explorations and percutaneous procedures of the breast in the exploration of a non-inflammatory palpable mass, in order to propose guidelines. METHOD: A systematic literature review was conducted in the Medline and Cochrane library databases. International guidelines in French and English language were also consulted until April 30th 2015. RESULTS: Physical examination of a non-inflammatory palpable breast mass is not sufficient to eliminate a breast cancer (LE2). Mammography alone has a sensitivity between 70 and 95% for the diagnosis of breast cancer (LE3). Echography alone has a sensitivity of 98 to 100% for the diagnosis of breast cancer (LE2). The core needle biopsy has a better sensitivity and specificity than the fine-needle aspiration for breast cancer diagnosis (LE2). The association of mammography and 2D echography presents excellent sensitivity and negative predictive value (close to 100 %) to exclude a breast cancer (LE3). A double evaluation using mammography and echography is recommended in the exploration of a non-inflammatory palpable breast mass (grade B).

[Benign breast tumors: Recommendations of Collège National des Gynécologues Obstétriciens Français (CNGOF)--Short text]. / Tumeurs bénignes du sein: recommandations pour la pratique clinique du Collège national des gynécologues et obstétriciens français (CNGOF)--Texte court.

Breast sonography is required with mammogram to explore clinical breast mass (grade B), colored unipore breast nipple discharge (grade C), or mastitis (grade C). Bi-RADS system is recommended to describe and classify breast-imaging abnormalities. For breast abscess, a percutaneous biopsy is recommended in case of mass or persistent symptoms (grade C). For mastodynia, when breast imaging is normal, no MRI neither breast biopsy is recommended (grade C). Percutaneous biopsy is recommended for BI-RADS 4-5 mass (grade B). For persistent erythematous breast nipple or atypical eczema lesion, a nipple biopsy is recommended (grade C). For distortion and asymmetry, a vacuum core needle biopsy is recommended because of the risk of underestimation by simple core needle biopsy (grade C). For BI-RADS 4-5 microcalcifications without ultrasound signal, a vacuum core needle biopsy of at least 11 gauges is recommended (grade B); in the absence of microcalcifications on radiograph carrots, additional samples are recommended (grade B). For atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, flat epithelial with atypia, radial scar, mucocele with atypia, surgical excision is commonly recommended (grade C). Expectant management is feasible after multidisciplinary concertation. For these lesions, when excision is not in sano, no new excision is recommended except for pleomorphic or with necrosis CLIS (grade C). For grade 1 phyllode tumour, in sano surgical resection is recommended; for grade 2 phyllode, 10-mm margins are recommended (grade C). For breast papillary without atypia, complete disappearance of the radiologic signal is recommended (grade C). For breast papillary with atypia, complete surgical excision is recommended (grade C).

Three-month efficacy and safety of once-daily diltiazem in chronic stable angina pectoris.

The 3-month efficacy and safety of a once-daily controlled formulation of diltiazem (180 to 360 mg/day) were assessed in a study of 54 patients with angina pectoris. This multicenter study was a nonrandomized, placebo run-in, open-label, 3-month trial followed by a 1-week, double-blind, randomized period during which most patients (89%) received placebo. There were only minimal changes in the time to termination (mean change +/- SEM -5.8 +/- 9.6 seconds), time to onset of angina (10.5 +/- 12.2 seconds), and the time to 1 mm ST-segment depression (2.9 +/- 12.5 seconds) from the end of the titration phase to the end of the open-label study. There were, however, statistically significant differences between the end of the 3-month treatment phase and the end of the 1-week randomized placebo phase for those 3 efficacy parameters (-37.3 +/- 11.2, -58.6 +/- 13.6, and -45.6 +/- 16.4 seconds, respectively). Diltiazem significantly decreased the frequency of anginal attacks and nitroglycerin use at the end of the 3-month treatment phase compared with results at the end of the randomized double-blind placebo phase. No new or unusual adverse events were reported during treatment. The present results suggest that there is no loss of efficacy of once-a-day diltiazem when administered for a long period to patients with chronic stable angina pectoris.

NMR and isotope ratio mass spectrometry studies of in vivo uptake and metabolism of polyunsaturates by the developing rat brain.

This article describes the application of in vivo 13C-nuclear magnetic resonance (NMR) spectroscopy and gas chromatography (GC)-combustion-isotope ratio mass spectrometry to the study of brain uptake and metabolism of polyunsaturated fatty acids in the suckling rat model. NMR spectroscopy is uniquely suited to the non-invasive detection of nonradioactive metabolites in living animals. We applied this approach to the noninvasive detection of 13C-arachidonate in brain and liver of living suckling rats but found that technical limitations in our model, mainly poor signal-to-noise, largely prevent useful results at this time. However, in a tracer study using simultaneous doses of 13C-gamma-linolenate and 13C-arachidonate, 13C-NMR of tissue lipid extracts quantitatively demonstrated a 10-fold greater (liver) or 17-fold greater (brain) accumulation of pre-formed vs newly synthesized arachidonate. GC-combustion-isotope ratio mass spectrometry was used to trace the utilization of [U-13C]-alpha-linolenate into three products in the brain: docosahexaenoate, cholesterol, and palmitate. The rationale was that although alpha-linolenate is used in de novo lipogenesis, the quantitative importance of this pathway is unknown. Our results in the suckling rat show that 2-13% of carbon from [U-13C]-alpha-linolenate appearing in brain lipids is in docosahexaenoate while the rest is in brain lipids synthesized de novo. Overall, these results indicate that the suckling rat brain prefers pre-formed to newly synthesized arachidonate and that alpha-linolenate is readily utilized in brain lipid synthesis. These methods are suited to comparative studies of the metabolism of polyunsaturates and they support previous observations that the metabolism of some polyunsaturates such as alpha-linolenate extends well beyond the traditional desaturation-chain elongation pathway.

Efficacy and Safety of Evening Administration of Controlled-Delivery Diltiazem Capsules in Chronic Stable Angina Patients.

The safety and efficacy of controlled-delivery (CD) once-a-day formulation of diltiazem administered in the evening, at a dose of 240 mg, was assessed in 37 patients with stable angina pectoris. A double-blind, placebo-controlled, randomized, crossover protocol was used. Following a 4-day washout period, patients entered a 5--7-day single-blind placebo run-in period during which qualification and reproducibility exercise treadmill tests (ETTs) were performed 24 h postdose. Eligible patients were randomized in a double-blind fashion, to either CD diltiazem or to placebo for a 7--10-day treatment period. They then entered a 5--7-day single-blind washout period, after which they received the alternate treatment for another 7 to 10 days. ETTs were performed at the end of each treatment period. Compared to placebo, evening administration of CD diltiazem produced a marked improvement of the time to ETT termination, time to onset of angina, and time to 1 mm ST depression. In addition, the number of angina attacks recorded in patient diaries was reduced compared to placebo. Incidence of adverse events was comparable with CD diltiazem and placebo. We conclude that evening administration of controlled-delivery diltiazem is highly effective and safe in the treatment of stable angina pectoris.

The role of diltiazem in treating hypertension and coronary artery disease: new approaches to preventing first events.

OBJECTIVE: To review the role of diltiazem in treating and preventing a group of cardiovascular diseases, including painful and silent cardiac ischemia, stroke, nonfatal myocardial infarction and sudden cardiac death, by modulating certain physiological causes that they appear to share. DATA SOURCES: A MEDLINE search was conducted for all clinical articles on the use of diltiazem for hypertension and coronary artery disease. When clinical data were not available, basic research findings were reviewed. DATA EXTRACTION AND SYNTHESIS: Because many cardiovascular events show a marked daily periodicity--which appears to coincide with circadian peaks in the ability of platelets to aggregate, sympathetic activity, coronary tone, blood pressure, heart rate and hematocrit, and a trough in fibrinolytic activity--the impact of diltizazem on these physiological changes was assessed. CONCLUSIONS: Diltiazem influences many of these events by increasing myocardial bloodflow, and reducing myocardial oxygen demand and cardiac workload. However, it differs from other calcium antagonists in its mild negative inotropic and moderate negative dromotropic effects, without apparent stimulation of cardiac performance or contractility. In addition, it inhibits platelet aggregation, decreases catecholamine release, diminishes coronary tone and blocks the vasoconstrictive actions of endothelin-1. This appears to translate into a beneficial effect on ischemia, thrombolysis, arrhythmias, infarct parameters, atherosclerosis and hypertension. Diltiazem has a relatively favourable safety and tolerability profile, and is available in a once-daily dosage form. The most common adverse effects are related to vasodilation (eg, edema and headache), and the most frequent serious adverse event is atrioventricular block, which occurs rarely. In summary, diltiazem appears to be well suited to preventing the first occurrence of cardiovascular events and may even have a role in preventing certain types of secondary events. The data accumulated so far indicate the need for a large scale random clinical trial addressing these outcomes.