SENIOR-NSTEMI: Should Elderly Patients with NSTEMI Receive Invasive Care?

Background: Non-ST-elevation myocardial infarction (NSTEMI) is defined as acute coronary injury resulting in ischemia and myocardial infarction. The diagnosis is made based on clinical presentation and non-specific electrocardiogram (ECG) changes including ST-segment depression, T-wave inversions, or other nonspecific findings.¹ Based on data from the NHS, most patients with NSTEMI are 70 years or older.² This, coupled with an increasing aging population, raises the question, what is the best management in patients 80 years old or older with NSTEMI?

Previous studies have attempted to evaluate the best approach to elderly patients with NSTEMI, but the mean age of patients was 66 years old with few patients over 80 years old leaving few data to extrapolate these results to this specific population age.³ The best means of obtaining data to answer clinical questions is through prospective randomized trials and there is an upcoming trial to answer this question specifically, the SENIOR-RITA (cool name) will not be expected to complete enrolment prior to 2029. In the meantime, this trial (SENIOR-NSTEMI) was conducted to provide further data regarding the best management of patients older than 80 years old with a NSTEMI.

Paper: Kaura A et al. Invasive Versus Non-Invasive Management of Older Patients with Non-ST Elevation Myocardial Infarction (SENIOR-NSTEMI): A Cohort Study Based on Routine Clinical Data. Lancet 2020. PMID: 32861307⁴ [Open in Read by QxMD]

Clinical Question: In patients ≥ 80 years of age with a NSTEMI is an invasive or non-invasive strategy associated with an improved mortality?

What They Did:

• Retrospective cohort study performed at 5 collaborating hospitals in the UK
• Patients who received invasive management for NSTEMI within 3 days of peak troponin were compared to those who did not receive invasive management
• Advanced statistics to account for immortality bias:
  • Immortality bias⁵: The period of follow up is too short for the endpoint or death to occur
    • Example: Patients who died prior to receiving invasive care for NSTEMI were classified in the noninvasive arm even though they may have received invasive care if they survived long enough to receive it.
  • Patients who died within 3 days of the peak troponin measurement were initially excluded and then included separately
    • Patients who were at extremes of too low risk and too high risk (10^th percentile) were excluded
    • Kaplan-Meier plot was created to display the cumulative risk of mortality and admission for heart failure in each group
      • Weighted for inverse probability of treatment to estimate risk
    • Patients were then re-included in the study based on intention-to-treat analysis
      • The ones that died within 3 days of peak troponin were randomly assigned to the invasive or noninvasive group based on propensity score

 Outcomes:

• Primary: All-cause mortality
• Secondary: Number of hospital admissions for heart failure during follow up

Inclusion:

• 80-years-old or older
• NSTEMI diagnosis

Exclusion:

• Patients with another acute illness resulting in a possible oxygen supply and demand mismatch i.e. another reason for an elevated troponin level
• 10^th percentile below propensity score (very likely to receive non-invasive management)
• 90^th percentile above propensity score (very likely to receive invasive management)

Results:

• 1976 patients included in the analysis
  • Median age of 86 years
    • Looked past the frailest and the healthiest using propensity scoring (375 patients)
    • Excluded patients who died within 3 days of peak troponin (101 patients)
  • 1500 patients included in the analysis
    • 56% invasive vs 44% non-invasive
    • 41% of patients died over the median follow up of 3 years
  • Primary outcome: 5-year mortality (inverse probability of treatment weighted Kaplan-Meier plots)
    • 36% in the invasive care group
    • 55% in the non-invasive care group
    • HR: 0.68 (95% CI 0.55 to 0.84)
  • Secondary outcome: Admission for heart failure (inverse probability of treatment weighted Kaplan-Meier plots)
    • 14% in the invasive care group
    • 19% in the non-invasive care group
    • RR 0.67 (95% CI 0.48 to 0.93)

Strengths:

• This is the largest study that attempts to evaluate the best approach for elderly patients (80-years-old and older) with NSTEMI
• Strong statistical analysis to adjust for immortal time bias when studying an aging population
• Strong statistical analysis to propensity score match patients in the invasive and non-invasive groups to determine the potential benefit of invasive versus non-invasive management of NSTEMI.

Limitations:

• Being a retrospective study, we can only infer associations and not causations related to invasive management of NSTEMI in elderly patients. The ongoing SENIOR-RITA will prospectively randomize patients 75 years old and older with NSTEMI to invasive or non-invasive management.
• Although strong statistical analysis and propensity score matching can help to equally match groups, confounding will still exist. Despite the fact that 70 potential confounding variables were included, there are some patient characteristics that cannot be accounted for in these analyses and without a proper randomized prospective trial. As a result of this, selection bias in invasive and non-invasive groups will still exist.
  • Patients in the invasive group were younger (85.3 vs 86.9 years old), had a higher rate of prior myocardial infarction (76% vs 56%), and an overall higher rate of cardiac risk factors including, hypertension (62% vs 54%), hypercholesterolemia (42% vs 30%), tobacco use (36% vs 18%), and family history of heart disease (16% vs 7%)
  • Patients in the non-invasive group had higher rates of renal disease including acute renal failure (9% vs 5%), urinary tract infection (7% vs 3%), as well as higher rates of respiratory disease including interstitial lung disease (3% vs 0.8%), pneumonia (9% vs 5%), and respiratory failure (3% vs 1%)
• There are other dangerous medical problems inherent with being over 80 years old, including cancer, that contribute to mortality in this age group.
• This study looks at all-cause mortality and does not address mortality specifically related to cardiac pathology.
• This study was conducted in the UK, and although the health systems and patients are similar, this should always be taken into account when attempting to extrapolate the data to a patient population in the United States.

Discussion:

Current European guidelines state, “conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure” but the “weight of evidence/opinion is in favour of usesfulness/efficacy.” When attempting to evaluate data from a new trial, we must see where it fits into what we already know about a topic. Unfortunately, there are not a lot of data regarding management of elderly patients with NSTEMI. The few trials looking at this question are briefly addressed below.

The After Eighty study⁶ was an open label study that looked at the composite outcome of MI, stroke, need for revascularization and death between 2010 and 2014 in Norway. The mean follow up time was 1.53 years. This study demonstrated 40.6% (of 229 patients) in the invasive group reached the primary outcome compared to 61.5% (of 228 patients) in the non-invasive group. The limitations of this study include its small size and open-label methodology. This study did assess bleeding complications and determined that there was no difference between the two groups.

The Italian Elderly ACS Trial⁷ randomized trial of patients aged 75-years-old or older with NSTEMI to an initial invasive or non-invasive group. The primary outcome was similar to the After Eighty study and included myocardial infarction, stroke, repeat hospital stay for CAD, and severe bleeding. 313 patients were randomized. This study demonstrated the primary outcome in 27.9% of the invasive group and 34.6% of the non-invasive group at one year. The limitations of this study include its small size.

Post-hoc analysis of the TATICS-TIMI 18⁸ demonstrated a composite of 6-month mortality, nonfatal MI, rehospitalization, stroke, and hemorrhagic complications in 10.8% of the invasive group compared to 21.6% of the non-invasive group for patients aged 75 and older. This trial did demonstrate a high risk of bleeding complications in patients aged 75 and older, 16.5% vs 6.5%. Of patients under 65, there was no difference in outcomes, 6.1% in the invasive group and 6.5% in the non-invasive group. Due to the post-hoc nature of this trial, the results should only be hypothesis generating, but this does address the potential harms of intervention when compared to benefits.

Based on the data from this study, invasive management of patients aged 80-years-old and older is associated with lower mortality and lower risk of admission to the hospital. Without a prospective randomized controlled study, these are the best data to help us determine the optimal management of elderly patients with NSTEMI.

In the interim, it is important to see how this trial fits into what we already know about management of NSTEMI based on the After Eighty study, Italian Elderly ACS Trials, post-hoc analysis of the TATICS-TIMI 18 trial. Based on the results of these studies and the SENIOR-NSTEMI study, there does appear to be a trend towards mortality improvement in invasive management of elderly patients. When determining the best management, we always have to include potential harms. Bleeding rates in this study were: 5.0% in the invasive group and 4.7% in the non-invasive group with an adjusted hazard ratio of 0.93 (95% CI 0.52 to 1.65), p = 0.801. There was an association of increased major bleeding in the post-hoc analysis of the TATICS-TIMI trial that in the invasive management group, but there was no difference in the After Eighty trial.

Author Conclusion: “On the basis of routinely collected clinical data from five UK tertiary centres we found that invasive management in patients aged 80 years or older with NSTEMI was associated with 32% lower mortality, compared with non-invasive management. The survival advantage bestowed by invasive management might extend to patients aged 80 years or older with NSTEMI.”

Clinical Take Home Point: There was an association of higher rates of survival at 5 years and fewer subsequent admissions for heart failure in elderly patients (≥ 80 years of age) who were diagnosed with an NSTEMI and underwent invasive management when compared to a non-invasive approach.

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References:

1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. PMID: 25249585; PMCID: PMC4676081
2. Myocardial Ischaemia National Audit Project. How the NHS cares for patients with heart attack. Annual Public Report April 2016 – March 2017. London: National Institute for Cardiovascular Outcomes Research, 2018. [Link is HERE]
3. Sinclair H, Kunadian V. Coronary revascularisation in older patients with non-ST elevation acute coronary syndromes. Heart PMID: 26740483
4. Kaura A et al. Invasive versus non-invasive management of older patients with non-ST elevation myocardial infarction (SENIOR-NSTEMI): a cohort study based on routine clinical data. Lancet. 2020. PMID: 32861307; PMCID: PMC7456783 [Open in Read by QxMD]
5. Lévesque LE, Hanley JA, Kezouh A, Suissa S. Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. BMJ. 2010. PMID: 20228141.
6. Tegn N, Abdelnoor M, Aaberge L, et al. Invasive versus conservative strategy in patients aged 80 years or older with non-ST-elevation myocardial infarction or unstable angina pectoris (After Eighty study): an open-label randomised controlled trial. Lancet 2016. PMID: 26794722
7. Savonitto S, Cavallini C, Petronio AS, et al. Early aggressive versus initially conservative treatment in elderly patients with non-ST-segment elevation acute coronary syndrome: a randomized controlled trial. JACC Cardiovasc Interv 2012. PMID: 22995877
8. Bach RG, Cannon CP, Weintraub WS, et al. The effect of routine, early invasive management on outcome for elderly patients with non-ST-segment elevation acute coronary syndromes. Ann Intern Med 2004. PMID: 15289215

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)