Adaptive Designs for Clinical Trials Bhatt, Deepak L; Mehta, Cyrus
New England journal of medicine/The New England journal of medicine,
2016-Jul-07, Volume:
375, Issue:
1
Journal Article
Although patients with cardiovascular disease face excess risks of severe illness with coronavirus disease-2019 (COVID-19), there may be indirect consequences of the pandemic on this high-risk ...patient segment.
This study sought to examine longitudinal trends in hospitalizations for acute cardiovascular conditions across a tertiary care health system.
Acute cardiovascular hospitalizations were tracked between January 1, 2019, and March 31, 2020. Daily hospitalization rates were estimated using negative binomial models. Temporal trends in hospitalization rates were compared across the first 3 months of 2020, with the first 3 months of 2019 as a reference.
From January 1, 2019, to March 31, 2020, 6,083 patients experienced 7,187 hospitalizations for primary acute cardiovascular reasons. There were 43.4% (95% confidence interval CI: 27.4% to 56.0%) fewer estimated daily hospitalizations in March 2020 compared with March 2019 (p < 0.001). The daily rate of hospitalizations did not change throughout 2019 (–0.01% per day 95% CI: –0.04% to +0.02%; p = 0.50), January 2020 (–0.5% per day 95% CI: –1.6% to +0.5%; p = 0.31), or February 2020 (+0.7% per day 95% CI: –0.6% to +2.0%; p = 0.27). There was significant daily decline in hospitalizations in March 2020 (–5.9% per day 95% CI: –7.6% to –4.3%; p < 0.001). Length of stay was shorter (4.8 days 25th to 75th percentiles: 2.4 to 8.3 days vs. 6.0 days 25th to 75th percentiles: 3.1 to 9.6 days; p = 0.003) and in-hospital mortality was not significantly different (6.2% vs. 4.4%; p = 0.30) in March 2020 compared with March 2019.
During the first phase of the COVID-19 pandemic, there was a marked decline in acute cardiovascular hospitalizations, and patients who were admitted had shorter lengths of stay. These data substantiate concerns that acute care of cardiovascular conditions may be delayed, deferred, or abbreviated during the COVID-19 pandemic.
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Acute coronary syndromes (ACS) are characterized by a sudden reduction in blood supply to the heart and include ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable ...angina. Each year, an estimated more than 7 million people in the world are diagnosed with ACS, including more than 1 million patients hospitalized in the US.
Chest discomfort at rest is the most common presenting symptom of ACS and affects approximately 79% of men and 74% of women presenting with ACS, although approximately 40% of men and 48% of women present with nonspecific symptoms, such as dyspnea, either in isolation or, more commonly, in combination with chest pain. For patients presenting with possible ACS, electrocardiography should be performed immediately (within 10 minutes of presentation) and can distinguish between STEMI and non-ST-segment elevation ACS (NSTE-ACS). STEMI is caused by complete coronary artery occlusion and accounts for approximately 30% of ACS. ACS without significant ST-segment elevation on electrocardiography, termed NSTE-ACS, account for approximately 70% of ACS, are caused by partial or intermittent occlusion of the artery and are associated with ST-segment depressions (approximately 31%), T-wave inversions (approximately 12%), ST-segment depressions combined with T-wave inversions (16%), or neither (approximately 41%). When electrocardiography suggests STEMI, rapid reperfusion with primary percutaneous coronary intervention (PCI) within 120 minutes reduces mortality from 9% to 7%. If PCI within 120 minutes is not possible, fibrinolytic therapy with alteplase, reteplase, or tenecteplase at full dose should be administered for patients younger than 75 years without contraindications and at half dose for patients 75 years or older (or streptokinase at full dose if cost is a consideration), followed by transfer to a facility with the goal of PCI within the next 24 hours. High-sensitivity troponin measurements are the preferred test to evaluate for NSTEMI. In high-risk patients with NSTE-ACS and no contraindications, prompt invasive coronary angiography and percutaneous or surgical revascularization within 24 to 48 hours are associated with a reduction in death from 6.5% to 4.9%.
Each year, an estimated more than 7 million people are diagnosed with ACS worldwide. For patients with STEMI, coronary catheterization and PCI within 2 hours of presentation reduces mortality, with fibrinolytic therapy reserved for patients without access to immediate PCI. For high-risk patients with NSTE-ACS without contraindications, prompt invasive coronary angiography followed by percutaneous or surgical revascularization is associated with lower rates of death.
The relationship between outpatient systolic and diastolic blood pressure and cardiovascular outcomes remains unclear and has been complicated by recently revised guidelines with two different ...thresholds (≥140/90 mm Hg and ≥130/80 mm Hg) for treating hypertension.
Using data from 1.3 million adults in a general outpatient population, we performed a multivariable Cox survival analysis to determine the effect of the burden of systolic and diastolic hypertension on a composite outcome of myocardial infarction, ischemic stroke, or hemorrhagic stroke over a period of 8 years. The analysis controlled for demographic characteristics and coexisting conditions.
The burdens of systolic and diastolic hypertension each independently predicted adverse outcomes. In survival models, a continuous burden of systolic hypertension (≥140 mm Hg; hazard ratio per unit increase in z score, 1.18; 95% confidence interval CI, 1.17 to 1.18) and diastolic hypertension (≥90 mm Hg; hazard ratio per unit increase in z score, 1.06; 95% CI, 1.06 to 1.07) independently predicted the composite outcome. Similar results were observed with the lower threshold of hypertension (≥130/80 mm Hg) and with systolic and diastolic blood pressures used as predictors without hypertension thresholds. A J-curve relation between diastolic blood pressure and outcomes was seen that was explained at least in part by age and other covariates and by a higher effect of systolic hypertension among persons in the lowest quartile of diastolic blood pressure.
Although systolic blood-pressure elevation had a greater effect on outcomes, both systolic and diastolic hypertension independently influenced the risk of adverse cardiovascular events, regardless of the definition of hypertension (≥140/90 mm Hg or ≥130/80 mm Hg). (Funded by the Kaiser Permanente Northern California Community Benefit Program.).
Summary Background Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor prevents ischaemic events after coronary stenting, but increases bleeding. Guidelines support weighting ...bleeding risk before the selection of treatment duration, but no standardised tool exists for this purpose. Methods A total of 14 963 patients treated with DAPT after coronary stenting—largely consisting of aspirin and clopidogrel and without indication to oral anticoagulation—were pooled at a single-patient level from eight multicentre randomised clinical trials with independent adjudication of events. Using Cox proportional hazards regression, we identified predictors of out-of-hospital Thrombosis in Myocardial Infarction (TIMI) major or minor bleeding stratified by trial, and developed a numerical bleeding risk score. The predictive performance of the novel score was assessed in the derivation cohort and validated in patients treated with percutaneous coronary intervention from the PLATelet inhibition and patient Outcomes (PLATO) trial (n=8595) and BernPCI registry (n=6172). The novel score was assessed within patients randomised to different DAPT durations (n=10 081) to identify the effect on bleeding and ischaemia of a long (12–24 months) or short (3–6 months) treatment in relation to baseline bleeding risk. Findings The PRECISE-DAPT score (age, creatinine clearance, haemoglobin, white-blood-cell count, and previous spontaneous bleeding) showed a c-index for out-of-hospital TIMI major or minor bleeding of 0·73 (95% CI 0·61–0·85) in the derivation cohort, and 0·70 (0·65–0·74) in the PLATO trial validation cohort and 0·66 (0·61–0·71) in the BernPCI registry validation cohort. A longer DAPT duration significantly increased bleeding in patients at high risk (score ≥25), but not in those with lower risk profiles (pinteraction =0·007), and exerted a significant ischaemic benefit only in this latter group. Interpretation The PRECISE-DAPT score is a simple five-item risk score, which provides a standardised tool for the prediction of out-of-hospital bleeding during DAPT. In the context of a comprehensive clinical evaluation process, this tool can support clinical decision making for treatment duration. Funding None.
Increases in lipid levels and cancers with tofacitinib prompted a trial of major adverse cardiovascular events (MACE) and cancers in patients with rheumatoid arthritis receiving tofacitinib as ...compared with a tumor necrosis factor (TNF) inhibitor.
We conducted a randomized, open-label, noninferiority, postauthorization, safety end-point trial involving patients with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor. The coprimary end points were adjudicated MACE and cancers, excluding nonmelanoma skin cancer. The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor.
A total of 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses (3.4% 98 patients and 4.2% 122 patients, respectively) than with a TNF inhibitor (2.5% 37 patients and 2.9% 42 patients). The hazard ratios were 1.33 (95% confidence interval CI, 0.91 to 1.94) for MACE and 1.48 (95% CI, 1.04 to 2.09) for cancers; the noninferiority of tofacitinib was not shown. The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor. Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion.
In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria. Several adverse events were more common with tofacitinib. (Funded by Pfizer; ORAL Surveillance ClinicalTrials.gov number, NCT02092467.).
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