BACKGROUND: Inflammation is associated with adverse cardiovascular events. Data from recent trials suggest that colchicine reduces the risk of cardiovascular events. METHODS: In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients who had myocardial infarction to receive either colchicine or placebo and either spironolactone or placebo. The results of the colchicine trial are reported here. The primary efficacy outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization, evaluated in a time-to-event analysis. C-reactive protein was measured at 3 months in a subgroup of patients, and safety was also assessed. RESULTS: A total of 7062 patients at 104 centers in 14 countries underwent randomization; at the time of analysis, the vital status was unknown for 45 patients (0.6%), and this information was most likely missing at random. A primary-outcome event occurred in 322 of 3528 patients (9.1%) in the colchicine group and 327 of 3534 patients (9.3%) in the placebo group over a median follow-up period of 3 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.16; P = 0.93). The incidence of individual components of the primary outcome appeared to be similar in the two groups. The least-squares mean difference in C-reactive protein levels between the colchicine group and the placebo group at 3 months, adjusted according to the baseline values, was -1.28 mg per liter (95% CI, -1.81 to -0.75). Diarrhea occurred in a higher percentage of patients with colchicine than with placebo (10.2% vs. 6.6%; P<0.001), but the incidence of serious infections did not differ between groups. CONCLUSIONS: Among patients who had myocardial infarction, treatment with colchicine, when started soon after myocardial infarction and continued for a median of 3 years, did not reduce the incidence of the composite primary outcome (death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization). (Funded by the Canadian Institutes of Health Research and others; CLEAR ClinicalTrials.gov number, NCT03048825.).
- MeSH
- C-reaktivní protein * analýza MeSH
- cévní mozková příhoda prevence a kontrola MeSH
- dvojitá slepá metoda MeSH
- infarkt myokardu * prevence a kontrola mortalita MeSH
- Kaplanův-Meierův odhad MeSH
- kolchicin * terapeutické užití škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- recidiva MeSH
- sekundární prevence MeSH
- senioři MeSH
- spironolakton terapeutické užití škodlivé účinky MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Atherosclerotic cardiovascular diseases (ACVDs), a condition characterised by lipid accumulation in arterial walls, which is often exacerbated by chronic inflammation disorders, is the major cause of mortality and morbidity worldwide. Colchicine, with its first medicinal use in ancient Egypt, is an inexpensive drug with anti-inflammatory properties. However, its role in primary prevention of ACVDs in the general population remains unknown. OBJECTIVES: To assess the clinical benefits and harms of colchicine as primary prevention of cardiovascular outcomes in the general population. SEARCH METHODS: We searched the Cochrane Heart Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, Web of Science, and LILACS. We searched ClinicalTrials.gov and WHO ICTRP for ongoing and unpublished studies. We also scanned the reference lists of relevant included studies, reviews, meta-analyses, and health technology reports to identify additional studies. There were no limitations on language, date of publication, or study setting. The search results were updated on 31 May 2023. SELECTION CRITERIA: Randomised controlled trials (RCTs) in any setting, recruiting adults without pre-existing cardiovascular disease. We included trials that compared colchicine versus placebo, non-steroidal anti-inflammatory drugs, corticosteroids, immunomodulating drugs, or usual care. Our primary outcomes were all-cause mortality, non-fatal myocardial infarction, stroke, and adverse events. DATA COLLECTION AND ANALYSIS: Two or more review authors independently selected studies, extracted data, and performed risk of bias and GRADE assessments. MAIN RESULTS: We identified 15 RCTs (1721 participants randomised; 1412 participants analysed) with follow-up periods ranging from 4 to 728 weeks. The intervention was oral colchicine compared with placebo, immunomodulating drugs, or usual care or no treatment. Due to biases and imprecision, the evidence was very uncertain for all outcomes. All trials but one had a high risk of bias. Five out of seven meta-analyses included fewer than six trials (71.4%). The objectives of the review were to assess cardiovascular outcomes in the general population, but many of the included trials focused on liver disease. Colchicine compared to placebo Colchicine may reduce all-cause mortality compared to placebo in primary prevention, but the evidence is very uncertain (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.51 to 0.91; 6 studies, 463 participants; very low-certainty evidence; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 6 to 67). Colchicine may result in little to no difference in non-fatal myocardial infarction, but the evidence is very uncertain (RR 0.87, 95% CI 0.41 to 1.82; 1 study, 100 participants; very low-certainty evidence). Colchicine may not reduce the incidence of stroke, but the evidence is very uncertain (RR 2.43, 95% CI 0.67 to 8.86; 1 study, 100 participants; very low-certainty evidence). Regarding adverse events, colchicine may increase the incidence of diarrhoea (RR 3.99, 95% CI 1.44 to 11.06; 8 studies, 605 participants; very low-certainty evidence; number needed to treat for an additional harmful outcome (NNTH) 10, 95% CI 6 to 17), and may have little to no effect on neurological outcomes such as seizure or mental confusion (RR 0.72, 95% CI 0.31 to 1.66; 2 studies, 155 participants; very low-certainty evidence), but the evidence is very uncertain. The effect of colchicine on cardiovascular mortality is also very uncertain (RR 1.27, 95% CI 0.03 to 62.43; 2 studies, 160 participants; very low-certainty evidence). Colchicine may not reduce post-cardiac procedure atrial fibrillation, but the evidence is very uncertain (RR 0.74, 95% CI 0.25 to 2.19; 1 study, 100 participants). We found no trials reporting on pericardial effusion, peripheral artery disease, heart failure, or unstable angina. Colchicine compared to methotrexate (immunomodulating drug) Colchicine may result in little to no difference in all-cause mortality compared to methotrexate, but the evidence is very uncertain (RR 0.42, 95% CI 0.12 to 1.51; 1 study, 85 participants; very low-certainty evidence). We found no trials reporting other cardiovascular outcomes or adverse events for this comparison. Colchicine compared to usual care or no treatment The evidence is very uncertain about the effect of colchicine compared with usual care on all-cause mortality in primary prevention (RR 1.07, 95% CI 0.90 to 1.27; 2 studies, 729 participants; very low-certainty evidence). Regarding adverse events, colchicine may increase the incidence of diarrhoea compared to usual care, but the evidence is very uncertain (RR 3.32, 95% CI 1.56 to 7.03; 2 studies, 729 participants; very low-certainty evidence; NNTH 18, 95% CI 12 to 42). No trials reported other cardiovascular outcomes for this comparison. AUTHORS' CONCLUSIONS: This Cochrane review evaluated the clinical benefits and harms of using colchicine for the primary prevention of cardiovascular events in the general population. Comparisons were made against placebo, immunomodulating medications, or usual care or no treatment. However, the certainty of the evidence for the predefined outcomes was very low, highlighting the pressing need for high-quality, rigorous studies to ascertain colchicine's clinical impact definitively. We identified numerous biases and inaccuracies in the included studies, limiting their generalisability and precluding a conclusive determination of colchicine's efficacy in preventing cardiovascular events. The existing evidence regarding colchicine's potential cardiovascular benefits or harms for primary prevention is inconclusive owing to the limitations inherent in the current studies. More robust clinical trials are needed to bridge this evidence gap effectively.
- MeSH
- antiflogistika nesteroidní terapeutické užití škodlivé účinky MeSH
- antiflogistika terapeutické užití škodlivé účinky MeSH
- cévní mozková příhoda prevence a kontrola mortalita MeSH
- infarkt myokardu * prevence a kontrola mortalita epidemiologie MeSH
- kardiovaskulární nemoci * prevence a kontrola mortalita MeSH
- kolchicin * terapeutické užití škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- příčina smrti MeSH
- primární prevence * metody MeSH
- randomizované kontrolované studie jako téma * MeSH
- zkreslení výsledků (epidemiologie) MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
- systematický přehled MeSH
The aim of the study was to examine the potential role of mitochondrial permeability transition pore (mPTP) in the cardioprotective effect of chronic continuous hypoxia (CH) against acute myocardial ischemia/reperfusion (I/R) injury. Adult male Wistar rats were adapted to CH for 3 weeks, while their controls were kept under normoxic conditions. Subsequently, they were subjected to I/R insult while being administered with mPTP inhibitor, cyclosporin A (CsA). Infarct size and incidence of ischemic and reperfusion arrhythmias were determined. Our results showed that adaptation to CH as well as CsA administration reduced myocardial infarct size in comparison to the corresponding control groups. However, administration of CsA did not amplify the beneficial effect of CH, suggesting that inhibition of mPTP opening contributes to the protective character of CH.
- MeSH
- chronická nemoc MeSH
- cyklosporin * farmakologie MeSH
- hypoxie * metabolismus MeSH
- infarkt myokardu metabolismus patologie prevence a kontrola MeSH
- krysa rodu rattus MeSH
- potkani Wistar * MeSH
- přechodový pór mitochondriální permeability * metabolismus MeSH
- reperfuzní poškození myokardu * metabolismus prevence a kontrola patologie MeSH
- srdeční mitochondrie metabolismus účinky léků patologie MeSH
- transportní proteiny mitochondriální membrány metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- HOBIT,
- MeSH
- cévní mozková příhoda * prevence a kontrola MeSH
- infarkt myokardu prevence a kontrola MeSH
- lidé MeSH
- odměny a ceny MeSH
- školy organizace a řízení MeSH
- zdravotní výchova * metody organizace a řízení MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
BACKGROUND: Atherosclerotic cardiovascular disease (ACVD) is worsened by chronic inflammatory diseases. Interleukin receptor antagonists (IL-RAs) and tumour necrosis factor-alpha (TNF) inhibitors have been studied to see if they can prevent cardiovascular events. OBJECTIVES: The purpose of this study was to assess the clinical benefits and harms of IL-RAs and TNF inhibitors in the primary and secondary prevention of ACVD. SEARCH METHODS: The Cochrane Heart Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, EBSCO CINAHL plus, and clinical trial registries for ongoing and unpublished studies were searched in February 2024. The reference lists of relevant studies, reviews, meta-analyses and health technology reports were searched to identify additional studies. No limitations on language, date of publication or study type were set. SELECTION CRITERIA: RCTs that recruited people with and without pre-existing ACVD, comparing IL-RAs or TNF inhibitors versus placebo or usual care, were selected. The primary outcomes considered were all-cause mortality, myocardial infarction, unstable angina, and adverse events. DATA COLLECTION AND ANALYSIS: Two or more review authors, working independently at each step, selected studies, extracted data, assessed the risk of bias and used GRADE to judge the certainty of evidence. MAIN RESULTS: We included 58 RCTs (22,053 participants; 21,308 analysed), comparing medication efficacy with placebo or usual care. Thirty-four trials focused on primary prevention and 24 on secondary prevention. The interventions included IL-1 RAs (anakinra, canakinumab), IL-6 RA (tocilizumab), TNF-inhibitors (etanercept, infliximab) compared with placebo or usual care. The certainty of evidence was low to very low due to biases and imprecision; all trials had a high risk of bias. Primary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality(RR 0.33, 95% CI 0.01 to 7.58, 1 trial), myocardial infarction (RR 0.71, 95% CI 0.04 to 12.48, I2 = 39%, 2 trials), unstable angina (RR 0.24, 95% CI 0.03 to 2.11, I2 = 0%, 2 trials), stroke (RR 2.42, 95% CI 0.12 to 50.15; 1 trial), adverse events (RR 0.85, 95% CI 0.59 to 1.22, I2 = 54%, 3 trials), or infection (rate ratio 0.84, 95% 0.55 to 1.29, I2 = 0%, 4 trials). Evidence is very uncertain about whether anakinra and cankinumab may reduce heart failure (RR 0.21, 95% CI 0.05 to 0.94, I2 = 0%, 3 trials). Peripheral vascular disease (PVD) was not reported as an outcome. IL-6 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.68, 95% CI 0.12 to 3.74, I2 = 30%, 3 trials), myocardial infarction (RR 0.27, 95% CI 0.04 to1.68, I2 = 0%, 3 trials), heart failure (RR 1.02, 95% CI 0.11 to 9.63, I2 = 0%, 2 trials), PVD (RR 2.94, 95% CI 0.12 to 71.47, 1 trial), stroke (RR 0.34, 95% CI 0.01 to 8.14, 1 trial), or any infection (rate ratio 1.10, 95% CI: 0.88 to 1.37, I2 = 18%, 5 trials). Adverse events may increase (RR 1.13, 95% CI 1.04 to 1.23, I2 = 33%, 5 trials). No trial assessed unstable angina. TNF inhibitors The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.78, 95% CI 0.63 to 4.99, I2 = 10%, 3 trials), myocardial infarction (RR 2.61, 95% CI 0.11 to 62.26, 1 trial), stroke (RR 0.46, 95% CI 0.08 to 2.80, I2 = 0%; 3 trials), heart failure (RR 0.85, 95% CI 0.06 to 12.76, 1 trial). Adverse events may increase (RR 1.13, 95% CI 1.01 to 1.25, I2 = 51%, 13 trials). No trial assessed unstable angina or PVD. Secondary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.94, 95% CI 0.84 to 1.06, I2 = 0%, 8 trials), unstable angina (RR 0.88, 95% CI 0.65 to 1.19, I2 = 0%, 3 trials), PVD (RR 0.85, 95% CI 0.19 to 3.73, I2 = 38%, 3 trials), stroke (RR 0.94, 95% CI 0.74 to 1.2, I2 = 0%; 7 trials), heart failure (RR 0.91, 95% 0.5 to 1.65, I2 = 0%; 7 trials), or adverse events (RR 0.92, 95% CI 0.78 to 1.09, I2 = 3%, 4 trials). There may be little to no difference between the groups in myocardial infarction (RR 0.88, 95% CI 0.0.75 to 1.04, I2 = 0%, 6 trials). IL6-RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.09, 95% CI 0.61 to 1.96, I2 = 0%, 2 trials), myocardial infarction (RR 0.46, 95% CI 0.07 to 3.04, I2 = 45%, 3 trials), unstable angina (RR 0.33, 95% CI 0.01 to 8.02, 1 trial), stroke (RR 1.03, 95% CI 0.07 to 16.25, 1 trial), adverse events (RR 0.89, 95% CI 0.76 to 1.05, I2 = 0%, 2 trials), or any infection (rate ratio 0.66, 95% CI 0.32 to 1.36, I2 = 0%, 4 trials). No trial assessed PVD or heart failure. TNF inhibitors The evidence is very uncertain about the effect of the intervention on all-cause mortality (RR 1.16, 95% CI 0.69 to 1.95, I2 = 47%, 5 trials), heart failure (RR 0.92, 95% 0.75 to 1.14, I2 = 0%, 4 trials), or adverse events (RR 1.15, 95% CI 0.84 to 1.56, I2 = 32%, 2 trials). No trial assessed myocardial infarction, unstable angina, PVD or stroke. Adverse events may be underestimated and benefits inflated due to inadequate reporting. AUTHORS' CONCLUSIONS: This Cochrane review assessed the benefits and harms of using interleukin-receptor antagonists and tumour necrosis factor inhibitors for primary and secondary prevention of atherosclerotic diseases compared with placebo or usual care. However, the evidence for the predetermined outcomes was deemed low or very low certainty, so there is still a need to determine whether these interventions provide clinical benefits or cause harm from this perspective. In summary, the different biases and imprecision in the included studies limit their external validity and represent a limitation to determining the effectiveness of the intervention for both primary and secondary prevention of ACVD.
- MeSH
- ateroskleróza * prevence a kontrola mortalita MeSH
- humanizované monoklonální protilátky * aplikace a dávkování škodlivé účinky MeSH
- infarkt myokardu * prevence a kontrola mortalita MeSH
- lidé MeSH
- nestabilní angina pectoris prevence a kontrola mortalita MeSH
- příčina smrti MeSH
- primární prevence * metody MeSH
- randomizované kontrolované studie jako téma MeSH
- receptory interleukinu-1 * antagonisté a inhibitory MeSH
- sekundární prevence * metody MeSH
- TNF-alfa * antagonisté a inhibitory MeSH
- zkreslení výsledků (epidemiologie) MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- systematický přehled MeSH
BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.
- MeSH
- cévní mozková příhoda prevence a kontrola MeSH
- hospitalizace statistika a číselné údaje MeSH
- infarkt myokardu prevence a kontrola MeSH
- ischemická cévní mozková příhoda * prevence a kontrola MeSH
- kolchicin * aplikace a dávkování terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- recidiva MeSH
- sekundární prevence * metody MeSH
- senioři MeSH
- tranzitorní ischemická ataka prevence a kontrola farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
A lack of adherence is associated with a worse prognosis. Decreasing adherence in post-MI patients leads to an increased risk of recurrence of ischemic events. In addition, due to the aging population and improved quality care for ACS with better survival, there is an increase in the number of patients who need more personalized secondary preventive interventions. For these patients, improving adherence is another way to improve their prognosis. The latest research shows that combination therapy, preferably in a fixed combination, should improve patient adherence and reduce the risk of CV disease complications. Thanks to the reduction in the number of tablets, the patient can stay on therapy for a longer period, because it is easier than using several tablets at once. The use of fixed combinations therapy in patients after MI as soon as possible, ideally already at discharge, leads to a significant improvement in adherence and a reduction in the risk of recurrence of ischemic events and a reduction in cardiovascular death, as demonstrated by the SECURE study. We should be able to ensure maximum patient adherence to treatment by administering fixed combinations of drugs with a proven efficacy especially an improvement of cardiovascular outcome.
Nedostatečná adherence je spojena s horší prognózou. Klesající adherence u pacientů po infarktu myokardu (IM) vede ke zvýšení rizika recidivy. Navíc kvůli stárnoucí populaci a kvalitní péči o nemocné s akutním koronárním syndromem (AKS) s lepším přežitím dochází k nárůstu počtu pacientů, kteří potřebují kvalitní sekundární prevenci. U těchto pacientů je zvýšení adherence další cestou ke zlepšení jejich prognózy. Poslední výzkumy ukazují, že kombinační terapie, nejlépe ve fixní kombinaci, může zlepšit adherenci pacientů a snížit riziko komplikací kardiovaskulárních onemocnění (KVO). Díky snížení počtu tablet je pacient schopen déle setrvat v nastavené terapii, protože je jednodušší než složitější léčebná schémata s větším počtem tablet. Využití fixních kombinací u pacientů po IM co nejdříve, ideálně již při propuštění, vede k významnému zlepšení adherence a ke snížení rizika recidivy a snížení úmrtí z kardiovaskulárních příčin, jak prokázala studie SECURE. Naší snahou by mělo být zajistit maximální adherenci pacientů k léčbě díky podávání fixních kombinací léků s prokázaným účinkem na prognózu KVO.
- MeSH
- adherence k farmakoterapii MeSH
- Aspirin terapeutické užití MeSH
- atorvastatin terapeutické užití MeSH
- fixní kombinace léků MeSH
- infarkt myokardu farmakoterapie prevence a kontrola MeSH
- kardiovaskulární nemoci * komplikace prevence a kontrola MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- ramipril terapeutické užití MeSH
- sekundární prevence MeSH
- Check Tag
- lidé MeSH
- MeSH
- infarkt myokardu * prevence a kontrola MeSH
- sekundární prevence * metody MeSH
- Publikační typ
- novinové články MeSH
- rozhovory MeSH
- MeSH
- infarkt myokardu * patologie prevence a kontrola MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- zprávy MeSH
