Cessation Events Research Articles

Reassessing the Safety of Varenicline

Reassessing the Safety of Varenicline

Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study

Dual antiplatelet therapy (DAPT) cessation increases the risk of adverse events after percutaneous coronary intervention (PCI). Whether risk changes over time, depends on the underlying reason for DAPT cessation, or both is unknown. We assessed associations between different modes of DAPT cessation and cardiovascular risk after PCI. The PARIS (patterns of non-adherence to anti-platelet regimens in stented patients) registry is a prospective observational study of patients undergoing PCI with stent implantation in 15 clinical sites in the USA and Europe between July 1, 2009, and Dec 2, 2010. Adult patients (aged 18 years or older) undergoing successful stent implantation in one or more native coronary artery and discharged on DAPT were eligible for enrolment. Patients were followed up at months 1, 6, 12, and 24 after implantation. Prespecified categories for DAPT cessation included physician-recommended discontinuation, brief interruption (for surgery), or disruption (non-compliance or because of bleeding). All adverse events and episodes of DAPT cessation were independently adjudicated. Using Cox models with time-varying covariates, we examined the effect of DAPT cessation on major adverse events (MACE [composite of cardiac death, definite or probable stent thrombosis, myocardial infarction, or target-lesion revascularisation]). Incidence rates for DAPT cessation and adverse events were calculated as Kaplan-Meier estimates of time to the first event. This study is registered with ClinicalTrials.gov, number NCT00998127. We enrolled 5031 patients undergoing PCI, including 5018 in the final study population. Over 2 years, the overall incidence of any DAPT cessation was 57·3%. Rate of any discontinuation was 40·8%, of interruption was 10·5%, and of disruption was 14·4%. The corresponding overall 2 year MACE rate was 11·5%, most of which (74%) occurred while patients were taking DAPT. Compared with those on DAPT, the adjusted hazard ratio (HR) for MACE due to interruption was 1·41 (95% CI 0·94-2·12; p=0·10) and to disruption was 1·50 (1·14-1.97; p=0·004). Within 7 days, 8-30 days, and more than 30 days after disruption, adjusted HRs were 7·04 (3·31-14·95), 2·17 (0·97-4·88), and 1·3 (0·97-1·76), respectively. By contrast with patients who remained on DAPT, those who discontinued had lower MACE risk (0·63 [0·46-0·86]). Results were similar after excluding patients receiving bare metal stents and using an alternative MACE definition that did not include target lesion revascularisation. In a real-world setting, for patients undergoing PCI and discharged on DAPT, cardiac events after DAPT cessation depend on the clinical circumstance and reason for cessation and attenuates over time. While most events after PCI occur in patients on DAPT, early risk for events due to disruption is substantial irrespective of stent type. Bristol-Myers Squibb and Sanofi-Aventis.

Association of smoking cessation and weight change with cardiovascular disease among adults with and without diabetes.

Smoking cessation reduces the risks of cardiovascular disease (CVD), but weight gain that follows quitting smoking may weaken the CVD benefit of quitting. To test the hypothesis that weight gain following smoking cessation does not attenuate the benefits of smoking cessation among adults with and without diabetes. Prospective community-based cohort study using data from the Framingham Offspring Study collected from 1984 through 2011. At each 4-year examination, self-reported smoking status was assessed and categorized as smoker, recent quitter (≤ 4 years), long-term quitter (>4 years), and nonsmoker. Pooled Cox proportional hazards models were used to estimate the association between quitting smoking and 6-year CVD events and to test whether 4-year change in weight following smoking cessation modified the association between smoking cessation and CVD events. Incidence over 6 years of total CVD events, comprising coronary heart disease, cerebrovascular events, peripheral artery disease, and congestive heart failure. After a mean follow-up of 25 (SD, 9.6) years, 631 CVD events occurred among 3251 participants. Median 4-year weight gain was greater for recent quitters without diabetes (2.7 kg [interquartile range {IQR}, -0.5 to 6.4]) and with diabetes (3.6 kg [IQR, -1.4 to 8.2]) than for long-term quitters (0.9 kg [IQR, -1.4 to 3.2] and 0.0 kg [IQR, -3.2 to 3.2], respectively, P < .001). Among participants without diabetes, age- and sex-adjusted incidence rate of CVD was 5.9 per 100 person-examinations (95% CI, 4.9-7.1) in smokers, 3.2 per 100 person-examinations (95% CI, 2.1-4.5) in recent quitters, 3.1 per 100 person-examinations (95% CI, 2.6-3.7) in long-term quitters, and 2.4 per 100 person-examinations (95% CI, 2.0-3.0) in nonsmokers. After adjustment for CVD risk factors, compared with smokers, recent quitters had a hazard ratio (HR) for CVD of 0.47 (95% CI, 0.23-0.94) and long-term quitters had an HR of 0.46 (95% CI, 0.34-0.63); these associations had only a minimal change after further adjustment for weight change. Among participants with diabetes, there were similar point estimates that did not reach statistical significance. In this community-based cohort, smoking cessation was associated with a lower risk of CVD events among participants without diabetes, and weight gain that occurred following smoking cessation did not modify this association. This supports a net cardiovascular benefit of smoking cessation, despite subsequent weight gain.

Dopamine-Related Genes and Spontaneous Smoking Cessation in Ever-Heavy Smokers

Several studies have provided evidence for associations of polymorphisms located in and near dopamine-related genes and nicotine dependence and other smoking-related phenotypes, including pharmacogenetic interactions. The purpose of the present work was to examine the association of SNPs in the DOPA decarboxylase (DDC), dopamine receptor D2 (DRD2) and dopamine transporter (SLC6A3) genes with smoking cessation in a large retrospective study featuring approximately 900 cessation events. Data originated from the enrollment questionnaire of the epidemiological ESTHER study of community-dwelling adults aged 50-74 years, conducted in the German state of Saarland between July 2000 and December 2002. Restricting the analyses to subjects who reported to have regularly smoked > 20 cigarettes per day at some point in their life, we used survival analysis methods to model the time from initiation of regular smoking to cessation (defined as quitting with abstinence lasting until enrollment) and its relation with eight polymorphisms in the aforementioned genes (five in DDC, two in DRD2 and one in SLC6A3) in 1446 participants. Neither individual variants nor DDC haplotypes were associated with the probability of overcoming nicotine dependence in this cohort. The repeated suggestion of associations between the variants examined and nicotine dependence in previous reports seems to contrast the negative results in the present study. This would appear consistent with the hypothesis that the establishment of regular heavy smoking might abolish associations between genetic determinants of nicotine dependence and nicotine dependence-related phenotypes, in particular the probability of successful smoking cessation.

Rare Fluctuations and Large-Scale Circulation Cessations in Turbulent Convection

In turbulent Rayleigh-Bénard convection, a large-scale circulation (LSC) develops in a nearly vertical plane and is maintained by rising and falling plumes detaching from the unstable thermal boundary layers. Rare but large fluctuations in the LSC amplitude can lead to extinction of the LSC (a cessation event), followed by the reemergence of another LSC with a different (random) azimuthal orientation. We extend previous models of the LSC dynamics to include momentum and thermal diffusion in the azimuthal plane and calculate the tails of the probability distributions of both the amplitude and azimuthal angle. Our analytical results are in very good agreement with the experimental data.

Relation between clopidogrel discontinuation and early cardiovascular events after percutaneous coronary intervention with drug-eluting stents

Clopidogrel discontinuation after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation has been reported to correlate with stent thrombosis. Whether these events are a consequence of the rebound phenomenon or a lack of protection in unhealed vessels is unclear. This study aimed to determine the link between clopidogrel cessation and cardiovascular events after PCI with DES. The population included 1,903 patients who underwent PCI with DES implantation from 2003 to 2007. We compared patients who stopped their clopidogrel within the first month (group 1, n=97), from one to six months (group 2, n=344), from six to 12 months (group 3, n=468), and after 12 months (group 4, n=994) following the PCI. In each group, the composite of death, myocardial infarction and stent thrombosis at 30 days and between 31 and 60 days after clopidogrel cessation was indexed. Baseline characteristics were similar among groups. The event rate observed in the 0-30 day interval following cessation was higher only in group 1 (5.2%) compared to all other groups: 1.2% (group 2), 0.9% (group 3) and 0.6% (group 4) (p=0.004). The event rates from 31 to 60 days following cessation were low and similar among the four groups. When the elapsed time between the index PCI and the clopidogrel cessation was analysed as a continuous variable, the probability of events occurring within the first 30 days became similar to that observed in the 31-60 day interval following cessation after a minimum of 10.2 months. Cardiac events seen immediately after clopidogrel cessation are not related to a rebound phenomenon, but are more likely influenced by the lack of healing at the time of cessation, which decreases over time. This increased risk related to the lack of healing seems to disappear after 10.2 months.

Variants in COMT and spontaneous smoking cessation: retrospective cohort analysis of 925 cessation events

Genome-wide studies have identified single nucleotide polymorphisms associated with smoking behaviour and nicotine dependence. Less is known about genetic determinants of smoking cessation, but rs4680 in COMT has recently been shown to explain a substantial proportion of the variation in cessation in the general population. We attempted to replicate the reported, clinically relevant effect in a population-based retrospective cohort analysis of 1443 ever-heavy smokers, of whom 925 had reached abstinence. In Cox regression models, neither rs4680 nor two polymorphisms nearby were associated with smoking cessation. The adjusted relative cessation rate (95% confidence interval) in rs4680 methionine carriers in reference to valine homozygotes was 0.97 (0.83-1.12). The absence of a significant effect of rs4680 in this statistically well-powered study - the 95% confidence interval even excluding the previously reported effect - highlights the need for rigorous replication efforts and suggests that rs4680 genotype should not yet be considered informative for smoking patient care.

Smoking Cessation and Variations in Nicotinic Acetylcholine Receptor Subunits α-5, α-3, and β-4 Genes

Evidence has recently accumulated that single nucleotide polymorphisms in the genetic region encoding the nicotinic acetylcholine receptor subunits alpha-5, alpha-3, and beta-4 are associated with smoking and nicotine dependence. We aimed to determine whether these genetic variations are also predictive of smoking cessation. Lifetime history of smoking was assessed by questionnaire at enrolment into a large epidemiological study of the German elderly population (ESTHER study). Cox proportional hazards modeling was applied in a retrospective cohort approach to determine the associations of individual polymorphisms and haplotypes with smoking cessation probability in 1446 subjects who reported regularly smoking more than 20 cigarettes at some point in their lives. Given the genotype distributions and number of cessation events observed, the power to detect associations ranged from 54% to 97% for hazard ratios of 1.2 to 1.4 in case of the variant with strongest prior evidence (alpha = .05). Nonetheless, neither individual polymorphisms nor inferred multilocus haplotypes were significantly associated with smoking cessation. Although the robust association of the nicotinic acetylcholine receptor subunit genes investigated with smoking-related phenotypes is an apparent success story of genetic epidemiology, the respective variations seem to exert no relevant influence on smoking cessation probability in heavy smokers in the general population.

Cessations and reversals of the large-scale circulation in turbulent thermal convection

We present an experimental study of cessations and reversals of the large-scale circulation (LSC) in turbulent thermal convection in a cylindrical cell of aspect ratio (Gamma) 1/2 . It is found that cessations and reversals of the LSC occur in Gamma = 1/2 geometry an order-of-magnitude more frequently than they do in Gamma=1 cells, and that after a cessation the LSC is most likely to restart in the opposite direction, i.e., reversals of the LSC are the most probable cessation events. This contrasts sharply to the finding in Gamma=1 geometry and implies that cessations in the two geometries are governed by different dynamics. It is found that the occurrence of reversals is a Poisson process and that a stronger rebound of the flow strength after a reversal or cessation leads to a longer period of stability of the LSC. Several properties of reversals and cessations in this system are found to be statistically similar to those of geomagnetic reversals. A direct measurement of the velocity field reveals that a cessation corresponds to a momentary decoherence of the LSC.

Effectiveness of smoking cessation therapies: a systematic review and meta-analysis.

BackgroundSmoking remains the leading preventable cause of premature deaths. Several pharmacological interventions now exist to aid smokers in cessation. These include Nicotine Replacement Therapy [NRT], bupropion, and varenicline. We aimed to assess their relative efficacy in smoking cessation by conducting a systematic review and meta-analysis.MethodsWe searched 10 electronic medical databases (inception to Sept. 2006) and bibliographies of published reviews. We selected randomized controlled trials [RCTs] evaluating interventions for smoking cessation at 1 year, through chemical confirmation. Our primary endpoint was smoking cessation at 1 year. Secondary endpoints included short-term smoking cessation (~3 months) and adverse events. We conducted random-effects meta-analysis and meta-regression. We compared treatment effects across interventions using head-to-head trials and when these did not exist, we calculated indirect comparisons.ResultsWe identified 70 trials of NRT versus control at 1 year, Odds Ratio [OR] 1.71, 95% Confidence Interval [CI], 1.55–1.88, P =< 0.0001). This was consistent when examining all placebo-controlled trials (49 RCTs, OR 1.78, 95% CI, 1.60–1.99), NRT gum (OR 1.60, 95% CI, 1.37–1.86) or patch (OR 1.63, 95% CI, 1.41–1.89). NRT also reduced smoking at 3 months (OR 1.98, 95% CI, 1.77–2.21). Bupropion trials were superior to controls at 1 year (12 RCTs, OR1.56, 95% CI, 1.10–2.21, P = 0.01) and at 3 months (OR 2.13, 95% CI, 1.72–2.64). Two RCTs evaluated the superiority of bupropion versus NRT at 1 year (OR 1.14, 95% CI, 0.20–6.42).Varenicline was superior to placebo at 1 year (4 RCTs, OR 2.96, 95% CI, 2.12–4.12, P =< 0.0001) and also at approximately 3 months (OR 3.75, 95% CI, 2.65–5.30). Three RCTs evaluated the effectiveness of varenicline versus bupropion at 1 year (OR 1.58, 95% CI, 1.22–2.05) and at approximately 3 months (OR 1.61, 95% CI, 1.16–2.21). Using indirect comparisons, varenicline was superior to NRT when compared to placebo controls (OR 1.66, 95% CI 1.17–2.36, P = 0.004) or to all controls at 1 year (OR 1.73, 95% CI 1.22–2.45, P = 0.001). This was also the case for 3-month data. Adverse events were not systematically different across studies.ConclusionNRT, bupropion and varenicline all provide therapeutic effects in assisting with smoking cessation. Direct and indirect comparisons identify a hierarchy of effectiveness.

Progressive hypoxia until brain electrical silence: a useful model for studying protective interventions

Anesthetized spontaneously breathing rats, fitted with epicortical electrodes and catheters for sampling arterial, venous, and cerebral venous blood, were exposed to standardized progressive hypoxia. Three minutes of hypoxia sequentially caused hyperpnea, hypopnea, apnea, and cessation of electrocorticogram "spiking," of synchronization, and of background in electroencephalogram (EEG). Blood data and cerebral blood flow and metabolism were measured throughout and at "insults," i.e., at apnea and cessation events, to clarify their interdependence. Arterial and brain venous PO2 fell linearly with inspired oxygen (final value of 2% at 280 s). Hyperpnea induced arterial alkalosis; subsequent hypopnea led to near-normal PCO2 and pH when EEG ceased. Hypercapnia was more pronounced in cerebral than in systemic venous blood; time courses of pH changes were similar. Sagittal sinus blood pressure and outflow were linearly related and resembled the time course of local cerebral blood flow. Blood flow increased by 25% at apnea and only 60% at EEG silence. Cerebral metabolic rate of O2 rose during the hyperpnea phase and fell exponentially thereafter. Cerebral glucose uptake and lactate release increased within the first 3 min but fell abruptly when cortico-electric spiking ceased. Time courses of cerebral O2 consumption and spike rate were linearly related; both showed inverse linear relations to cerebral perfusion. The hypoxic insults were well defined by blood data; critical PO2 values were lower than previously assumed. This model is proving to be a useful, controlled method by which mechanisms of cerebral hypoxia tolerance may be studied in vivo.

Phenology of Sumacs

The nature and extent of phenological variability among individuals of sumac, Rhus glabra, was investigated. The phenological events considered are: bud elongation, bud opening, leaf appearance, cessation of leaf and twig growth, inflorescence appearance, first flower and fruit, and cessation of inflorescence growth. The sex of the clone, height of the stem above ground, age -of the stem, and the final twig length showed association with phenological events. Phenological stages are grouped into the cessation events which develop slowly throughout the clone, and the developmental events which occur rapidly throughout the clone. Through the use of a multiple range test, the mean values of all clones for each event can be grouped into those which show no statistical difference from each other. The number of times one clone is grouped with another may be considered an index of the phenological similarity of the clones. The major conclusions drawn are: (1) the phenological variability appears to be primarily associated with the genetic constitution of the plant; (2) aspects of the structure and life history of the clone seem associated to a lesser extent with its phenology; (3) exposure of the clone on the hilltop and exposure of the stem within the clone seem to have no effect on the phenology.