Join us as we review recent practice-changing articles addressing the questions: Do weekend warriors experience a mortality benefit from exercise? Is an aggressive fluid strategy superior to a moderate strategy in acute pancreatitis? Does an invite for colonoscopy decrease colon cancer-related mortality? Did the benefits of intensive blood pressure control continue after the SPRINT trial ended? Fill your plate with a stack of hot tofurkey cakes! Featuring Drs. Era Kryzhanovskaya (@erakryzhmd), Nora Taranto (@norataranto), Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), and Matt Watto (@doctorwatto).
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Deep dives on practice-changing articles.
Dos Santos M, et al. Association of the “Weekend Warrior” and Other Leisure-time Physical Activity Patterns With All-Cause and Cause-Specific Mortality: A Nationwide Cohort Study. JAMA Intern Med. 2022 Aug 1;182(8):840-848. doi: 10.1001/jamainternmed.2022.2488. PMID: 35788615; PMCID: PMC9257680.
Question: Does performing the recommended levels of weekly physical activity in 1 to 2 sessions (weekend warrior) vs three or more sessions (regularly active) influence mortality benefit from exercise?
Comparison: This nationwide prospective cohort study included adults with self-reported physical activity data in the US National Health Interview Survey from 1997 to 2013. Outcomes (all-cause mortality, cardiovascular mortality, and cancer mortality) were obtained from the National Death Index through December 31, 2015. Participants were grouped by physical activity level: physically inactive (<150 minutes per week [min/wk] of moderate-to-vigorous physical activity [MVPA]) or physically active (≥150 min/wk of MVPA). The active group was further classified by pattern: weekend warrior (1-2 sessions/wk) or regularly active (≥3 sessions/wk); and then, by frequency, duration/session, and intensity of activity.
Results: A total of 350,978 participants were followed for a median of 10.4 years (contributing a total of 3.6 million person-years). Controlling for the total amount of MVPA, weekend warrior participants had similar all-cause and cause-specific mortality rates as regularly active participants. The HRs for weekend warrior vs regularly active participants were 1.08 (95% CI, 0.97-1.20) for all-cause mortality; 1.14 (95% CI, 0.85-1.53) for CVD mortality; and 1.07 (95% CI, 0.87-1.31) for cancer mortality.
Limitations: This was an observational study, so cannot determine more than just associations (ie, not causality). But this was a huge study and had median 10-year follow-up (and, it might be a tad difficult to perform an actual RCT, randomizing lots of people to varying degrees of exercise and varying numbers of days of exercise/week, and including people with a variety of baseline underlying conditions, and following them 10 years…). Also, the definition of “physically inactive” includes people who exercise below the recommended amount, biasing towards a null finding.
Bottom Line: EXERCISE is MORTALITY REDUCING! Doesn’t matter if done frequently in small aliquots or similar amounts in 1-2 days (easier for more folks who can’t fit it in after/before work!).
Lee DH, Rezende LFM, Joh HK, et al. Long-Term Leisure-Time Physical Activity Intensity and All-Cause and Cause-Specific Mortality: A Prospective Cohort of US Adults. Circulation. 2022;146:523–534. Originally published 25 Jul 2022. https://doi.org/10.1161/CIRCULATIONAHA.121.058162
Resistance training at least twice each week lowers mortality in adults 65 and over
Shoutout and big thanks to Dr. Geoff Modest whose weekly lit-review emails brought this weekend warrior article to our attention and whose impeccable digest of the methods and implications of the results of this study made for a great launching point for our critical appraisal discussion! You can sign up for his blogs by emailing him at email@example.com
Brief discussion of recent articles, medical news, guidelines
de-Madaria E, Buxbaum JL, et al; ERICA Consortium. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N Engl J Med. 2022 Sep 15;387(11):989-1000. doi: 10.1056/NEJMoa2202884. PMID: 36103415.
Question: Is a moderate fluid resuscitation strategy safe and effective, compared with aggressive fluid resuscitation, in the prevention of complications of pancreatitis?
Comparison: 249 patients hospitalized with acute pancreatitis (diagnosed by having 2 of 3 revised Atlanta criteria: epigastric pain, amylase or lipase elevation, or imaging evidence of pancreatitis) who presented with 24 hours of symptom onset were included. Patients with moderate or severe pancreatitis were excluded, as were patients with congestive heart failure, uncontrolled hypertension, electrolyte disturbances, limited life expectancy, chronic pancreatitis, chronic kidney disease, or decompensated cirrhosis. Patients were randomized in an open-label fashion to receive lactated ringers dosed as “aggressive” (a bolus of 20 mL/kg, followed by 3 mL/kg/hr), or “moderate” (a bolus of 10 mL/kg only if hypovolemic, followed by 1.5 mL/kg/hr). Fluids were stopped once patients were eating.
Results: This was a negative study, and it was stopped early due to evidence of harm: the primary efficacy outcome, a composite reflecting the development of moderate/severe pancreatitis during hospitalization (local complications, exacerbation of other underlying diseases, Cr >1.9, SBP <90, P:F ratio <300), occurred in 22% of the aggressive group, and 17% of the moderate group (RR 1.30, 95% CI 0.78-2.18). The primary safety outcome, volume overload (diagnosed by symptoms, signs, or imaging), occurred in 21% of the aggressive group, and 6% of the moderate group (RR 2.85, 95% CI 1.36-5.94). Subgroup analyses did not suggest that patients with systemic inflammatory response syndrome (SIRS) criteria or hypovolemia benefitted from aggressive resuscitation.
Limitations: Because the study was stopped early, it is tempting to ask if it could have been underpowered for the primary efficacy outcome. I don’t think this is likely because the point estimates do not suggest imprecise estimation of a lower rate of complications in the aggressive group. The open-label nature of the study could have led to ascertainment bias in the detection of volume overload, but the large effect size makes me think it is unlikely that ascertainment bias completely explains it.
Bottom line: Aggressive fluid resuscitation did not lead to better outcomes in patients with pancreatitis, but it did lead to more frequent volume overload. This well-done study should prompt reconsideration of aggressive fluid resuscitation in acute pancreatitis.
Hotcakes rating: 5 out of 5
Tenner S, Baillie J, DeWitt J, Vege SS; American College of Gastroenterology. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol 2013; 108: 1400-16.
Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence based guidelines for the management of acute pancreatitis. Pancreatology 2013;13: Suppl 2: e1-e15.
Bretthauer M, et al; NordICC Study Group. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death. N Engl J Med. 2022 Oct 27;387(17):1547-1556. doi: 10.1056/NEJMoa2208375. Epub 2022 Oct 9. PMID: 36214590.
Question: Do colonoscopies decrease the risk of colorectal cancer (CRC), and do they decrease the risk of CRC-related mortality and overall mortality, compared with no CRC screening? To this point, we’ve primarily relied on cohort studies to estimate the benefit of screening colonoscopy (thought to be around a 40-69% decrease in the incidence of CRC, and 29-88% decrease in the risk of death from CRC). And the USPSTF made a general recommendation in its latest 2021 screening guidelines, recommending screening for CRC (but no particular screening modality) starting at age 45.
Comparison: The NordICC study group randomized almost 85,000 healthy men and women between 55 and 64 years of age to receive an invitation to undergo a screening colonoscopy or to receive no such invitation to undergo screening. This study occurred in Poland, Norway, Sweden, and the Netherlands among individuals who had not undergone screening before. The primary outcomes were the risk of CRC and CRC-related death, with a key secondary endpoint being death from any cause.
Results: This was a pragmatic trial, to reflect real-world clinical practice. In the intention-to-screen analysis: Invitation to a one-time screening colonoscopy resulted in a decreased risk of colon cancer over a median follow-up of 10 years, with a relative risk reduction of 18% between the invited group versus the usual care group (0.98% risk in the invited group, and 1.2% in the usual-care group). The “number needed to invite” was 455 individuals to prevent one case of colorectal cancer over 10 years. However, there was no significant difference in the risk of death from colorectal cancer (risk ratio 0.90, 95% CI 0.64 – 1.16), and risk of death overall (risk ratio 0.99, CI 0.96 – 1.04). Notably, only 42% of those invited actually underwent screening colonoscopy. In the per-protocol analysis (where the effect of screening was quantified if all participants who were randomly assigned to the invited group had actually undergone screening), the risk ratio for CRC was 0.69 (95% CI 0.55 – 0.83), and the risk of death from CRC of 0.15% in the invited group and 0.30% in the usual-care group (risk ratio of 0.5, CI 0.27 – 0.77). There was very little contamination of the control arm.
Bottom Line: In this pragmatic trial, colonoscopy screening reduced the risk of colorectal cancer at 10 years, but not the risk of death from colorectal cancer or death from any cause. Colonoscopy screening is the most common screening modality recommended in the United States, but this trial did not find a mortality benefit from colonoscopy screening (either CRC-specific or all-cause). Compare these data to those supporting flexible sigmoidoscopy in randomized trials (4 trials, demonstrating decreased CRC-specific mortality). Is the benefit of evaluating the “whole bowel” with colonoscopy, compared to sigmoidoscopy, really worth it?
NEJM Editorial: Understanding the results of a randomized trial of screening colonoscopy
USPSTF 2021 Colorectal Cancer Screening Guidelines
Jaeger BC, et al. Longer-Term All-Cause and Cardiovascular Mortality With Intensive Blood Pressure Control: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2022 Oct 12:e223345. doi: 10.1001/jamacardio.2022.3345. Epub ahead of print. PMID: 36223105; PMCID: PMC9558058.
Question: Did the cardiovascular and all-cause mortality of intensive blood pressure control seen in the SPRINT trial persist after completion of the trial? The authors examined both mortality as well as blood pressure control after completion of the SPRINT trial. Your gentle reminder that the SPRINT trial examined the effects of intensive systolic blood pressure control (<120 mm Hg) compared to standard control (<140 mm Hg) in patients with elevated cardiac risk (clinical or subclinical CVD, CKD, Framingham risk score >15%, or age greater than 75 years). Emphasis was made on appropriate measurement, and the patients had frequent follow-ups. A reminder also that the trial was stopped early at 3.3 years due to the significant mortality benefits seen in the intensive arm.
Comparison: The comparison here is interesting to me, because it is looking at patients at the end of a study, and comparing the results to time extrapolated out after completion. The authors linked the trial participants to the national death index (NDI) from 2016 through 2020, effectively adding 4.5 years of follow-up to the study’s conclusion. For blood pressure, they extracted longitudinal data of systolic blood pressure from 2010 to 2020 (2944 patients out of the >9000 from the SPRINT trial).
Results: The all-cause mortality benefit attenuated over time following a period of initial benefit in the intensive arm from 1 to 2.8 years. Similarly, CV mortality benefit was seen in the intensive arm from 2.3 to 5.6 years but attenuated through the remainder of the observational phase. The average systolic blood pressure of participants in the intensive arm was 132.8 mm Hg at 5 years following randomization and 140.4 mm Hg at 10 years, compared to 138.8 mm Hg in the standard treatment arm at 5 years and 140.2 mm Hg at 10 years.
Bottom Line: The cardiovascular and all-cause mortality benefits seen in the intensive arm of the SPRINT trial attenuated over time after completion of the trial. There are several reasons for this. First, the fact that the SPRINT trial ended early increases the likelihood that the benefit was overestimated. There was also a loss of the blood pressure control achieved in SPRINT which is not all that surprising. The patients were no longer undergoing the study protocols and were probably not having their blood pressure measured in a protocolized way. Additionally, the clinicians that they returned to may not have been aware of the SPRINT benefits and may have been less aggressive. Finally, it may be harder to treat hypertension the older patients get. What this trial does suggest is that for the benefits of intensive control to persist, clinicians must remain vigilant and aggressive in managing the blood pressure of their older patients.
Hotcakes rating: 3 or whatever.
JAMA commentary – Blood Pressure Control After SPRINT – back to reality
Stopping Randomized Trials Early for Benefit and Estimation of Treatment Effects
Listeners will review recent practice-changing articles and medical news.
After listening to this episode listeners will…
The Curbsiders report no relevant financial disclosures.
Kryzhanovskaya E, Taranto NP, Ganatra RB, Williams PN, Watto MF. “#367 Weekend Warriors, Fluids for Acute Pancreatitis, Colonoscopy Screening & Mortality, and SPRINT trial Revisited (Hotcakes)”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list Final publishing date November 21, 2022.
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