betablocker post MI clinical trial , for herat faliure with presered EF

bb post mi

1. Published on the 7TH of APRIL ,2024 Presented by : Adel jaffal , MD 15/5/2024

2. Outline BACKGROUND Methods Randomization and Follow-up End Points Results Discussion

3. BACKGROUND The efficacy of beta-blockers in patients with heart failure and reduced ejection fraction is well documented. Trials have also shown that long-term beta-blocker therapy after myocardial infarction reduces mortality by approximately 20%.

4. BACKGROUND However, these results are from trials that mainly involved patients with large myocardial infarctions and left ventricular systolic dysfunction and were conducted primarily in the 1980s . This era predates advancements such as high-sensitivity cardiac troponins, percutaneous coronary interventions, antithrombotic agents, high-intensity statins, and renin–angiotensin–aldosterone system antagonists.

5. BACKGROUND A meta-analysis suggested that in the era of modern reperfusion strategies, beta-blockers did not significantly reduce mortality. Data on the effect of long-term beta-blocker therapy in patients with acute myocardial infarction and preserved ejection fraction are lacking from contemporary, sufficiently powered, randomized clinical trials.

6. BACKGROUND Despite the lack of clear evidence of benefit in the contemporary setting, current guidelines widely recommend beta-blocker use after myocardial infarction. We conducted a trial (Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction [REDUCE-AMI]) to investigate whether long-term oral beta-blocker treatment in patients with acute myocardial infarction and preserved left ventricular ejection fraction would lead to a lower risk of a composite end point of death of any cause or new myocardial infarction than no beta-blocker use.

7. Methods We conducted this registry-based, prospective, open-label, parallel-group, randomized clinical trial in three countries: Sweden (38 centers), Estonia (1 center), and New Zealand (6 centers). The trial was overseen by a data and safety monitoring board, which performed two interim analyses of patient safety.

8. Methods Adult patients who provided written informed consent 1 to 7 days after myocardial infarction and who had undergone coronary angiography and echocardiography with a preserved left ventricular ejection fraction (≥50%) were eligible. Patients were also required to have obstructive coronary artery disease as documented by coronary angiography (i.e., stenosis of ≥50%) at any time point before randomization.

9. Methods Major exclusion criteria were an indication for or contraindication to beta-blocker treatment. To ensure completeness of follow-up, nonresidents of the three trial countries could not undergo randomization.

10. Inclusion criteria Men or women age ≥18 at the time of signing the informed consent Day 1-7 after MI, either ST elevation MI or non-ST-elevation MI, Coronary angiography performed during hospitalization. Obstructive coronary artery disease documented by coronary angiography, i.e. stenosis ≥ 50 %. Echocardiography performed after the MI showing a normal ejection fraction defined as EF≥50%. Written informed consent obtained

11. Exclusion criteria 1. Any condition that may influence the patient’s ability to comply with study protocol. 2. Contraindications for beta-blockade . 3. Indication for beta-blockade other than as secondary prevention according to the treating physician.

12. Randomization Randomization was stratified according to trial center and was performed in a 1:1 ratio with the use of permuted blocks; trial groups were assigned by means of a Web-based system.

13. Methods Patients who were randomly assigned to the betablocker group were administered metoprolol (first choice) or bisoprolol (alternative) during the remaining hospital stay and received a prescription for continued use after discharge. The treating physician was encouraged to aim for a dose of at least 100 mg daily for metoprolol and at least 5 mg daily for bisoprolol.

14. Methods Patients were encouraged to continue the use of beta-blockers after discharge until the occurrence of a contraindication. Patients who were randomly assigned to the no–beta-blocker group were discouraged from using beta-blockers as long as there was no other indication than secondary prevention after myocardial infarction.

15. For blood-pressure control, drugs other than beta-blockers were recommended according to guidelines. If a patient was already receiving treatment with a beta-blocker when enrolled and randomly assigned to the no–beta-blocker group, a tapering of the beta-blocker had to be carried out during a period of 2 to 4 weeks. Methods

16. Methods The importance of continuation of the assigned regimen (beta-blockers or no beta-blockers) was documented in patients’ health records. Patients received written information explaining the importance of continuing the assigned regimen unless contraindications to beta-blockers or indications for beta-blockers other than for secondary prevention arose. The patient also received a summary of this information in an identification card–size format to wear in case of medical contact.

17. Clinical End Points The primary end point was a composite of death from any cause or new myocardial infarction. Secondary end points were death from any cause, death from cardiovascular causes, myocardial infarction, hospitalization for atrial fibrillation (as a primary diagnosis), and hospitalization for heart failure (as a primary diagnosis).

18. Clinical End Points Safety end points were hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker; hospitalization for asthma or chronic obstructive pulmonary disease (as a primary diagnosis); and hospitalization for stroke .

19. Clinical End Points Angina pectoris (according to Canadian Cardiovascular Society class) and dyspnea (according to New York Heart Association class) after 6 to 10 weeks and after 11 to 13 months were also end points.

20. Secondary outcomes 1. First occurrence of symptomatic stroke (ischemic or hemorrhagic stroke). 2. Acute coronary syndrome (myocardial infarction and hospitalization for unstable angina). 3. Hospitalization for acute decompensated heart failure. 4. Coronary revascularization (PCI or CABG) 5. Atrial fibrillation. 6. Cardiovascular death. Cardiovascular death includes fatal coronary heart disease, fatal stroke, death from heart failure, and sudden cardiac death. 7. All-cause mortality. 8. Major adverse cardiac events .

21. 9. Decline in renal function or development of end stage renal disease. (1) For patients with chronic kidney disease (estimated glomerular filtration rate[ eGFR ] < 60 ml per minute per 1.73 m2) at baseline, a decrease in the eGFR of ≥ 50% (confirmed by a subsequent laboratory test) or the development of end stage renal disease requiring long-term dialysis or kidney transplantation. For participants without chronic kidney disease at baseline, a decrease in the eGFR of ≥ 30% to a value of < 60 ml per minute per 1.73 m2 ; or (2) Serum creatinine increases 1.5 mg/ dL or more in men, > 1.3 mg/ dL or more in women; or (3) eGFR < 30ml/min/1.73 m2 .

22. 10. Decline in cognitive function. Decline in cognitive function includes sensory disturbance, memory disorders and thinking disorders, which is assessed by mini-mental state examination (MMSE). MMSE is a sum-score, evaluating various dimensions of cognition, used as an index of global cognitive performance. Scores on the MMSE range from 0 to 30, with higher scores indicating better cognition.

23. 11. Major artery stiffness. 12. First occurrence of diabetes mellitus

24. Results Of the 9624 patients screened at 42 clinical centers throughout China, 1113 (11.6%) were excluded. A total of 8511 patients 60 to 80 years of age were randomly assigned to the intensive-treatment group (4243 patients) or the standard-treatment group (4268 patients). A total of 234 patients (2.7%) were lost to follow-up before the end of the trial

25. Clinical Outcomes During the median follow-up period of 3.34 years, primary-outcome events occurred in 147 of 4243 patients (3.5% [1.0% per year]) in the intensive treatment group, as compared with 196 of 4268 patients (4.6% [1.4% per year]) in the standard treatment group (hazard ratio, 0.74; 95% CI, 0.60 to 0.92; P = 0.007). The incidence of primary- outcome events was significantly lower in the intensive-treatment group than in the standard treatment group, with an absolute difference of 1.1 percentage points .The results for most of the secondary outcomes also favored intensive treatment

26. Safety and Renal Outcomes The incidences of dizziness, syncope, and fracture and the results for renal outcomes did not differ significantly between the two trial groups , nor did the incidences of angioedema , headache, cough, and hives. However, the incidence of hypotension was significantly higher in the intensive-treatment group than in the standard-treatment group (3.4% vs. 2.6%, P = 0.03).

27. Discussion Several large trials have shown a beneficial effect of intensive blood-pressure control on cardiovascular outcomes in older patients, but the appropriate systolic blood-pressure target remains unclear. Our large trial provides important evidence, showing that a reduction in the systolic blood pressure to less than 130 mm Hg resulted in cardiovascular benefits in older patients with hypertension in China Comparison of the STEP trial with SPRINT is interesting; intensive blood-pressure control resulted in cardiovascular benefits in both trials

28. Discussion Several major differences between the trials should be noted In SPRINT, office blood pressure was measured with the use of an automated system, and trial staff were not present during the rest period, when the measurement was taken, or throughout the entire process. In the STEP trial, office blood pressure was measured by trained trial staff with the use of an oscillometric electronic sphygmomanometer; with this blood pressure monitor, only the inflating procedure is automated.

29. Discussion SPRINT excluded persons with diabetes mellitus, whereas the STEP trial did not. Both trials excluded persons with a history of Stroke .

30. Discussion Although SPRINT showed that a systolic blood-pressure target of less than 120 mm Hg was associated with cardiovascular benefits, practical issues have been raised with regard to this treatment strategy. Such a low systolic blood-pressure target is challenging to reach and can result in higher medication costs and more frequent clinic visits.

31. Discussion In addition, a significantly increased incidence of kidney injury was observed with a systolic blood-pressure target of less than 120 mm Hg among participants without chronic kidney disease in SPRINT; an increased incidence of kidney injury was not observed with a systolic blood-pressure target of 110 to less than 130 mm Hg in the STEP trial

32. Of note, the incidence of hypotension increased significantly with intensive blood-pressure control in both trials. Previous studies have shown that, among older people with a pulse pressure of more than 60 mm Hg or a diastolic blood pressure of less than 60 mm Hg (or both), a very low systolic blood pressure might increase the risk of subclinical myocardial ischemia and recurrent stroke. Caution is warranted when aiming for lower systolic blood-pressure targets among older patients, particularly those who have stiff arteries.

33. The STEP trial showed that a systolic blood pressure target of 110 to less than 130 mm Hg was associated with reduced risks of stroke and acute coronary syndrome in older patients with hypertension, but similar results were not observed in SPRINT. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that a systolic blood-pressure target of less than 120 mm Hg was associated with a reduced risk of stroke. In the STEP trial, intensive treatment did not have a significant effect on the risk of death from cardiovascular causes (hazard ratio, 0.72; 95% CI, 0.39 to 1.32) or the risk of death from any cause (hazard ratio, 1.11; 95% CI, 0.78 to 1.56);

34. in SPRINT, intensive treatment led to significantly reduced risks of death from cardiovascular causes (hazard ratio, 0.58; 95% CI, 0.39 to 0.84) and death from any cause (hazard ratio, 0.75; 95% CI, 0.61 to 0.92). In addition, the annual event rates for the primary outcome in the intensive-treatment group and the standard-treatment group observed in the STEP trial (1.0% per year and 1.4% per year, respectively) were lower than those observed in SPRINT (1.77% per year and 2.40% per year, respectively).

35. The difference between the STEP trial and SPRINT in the risks of death from any cause and death from cardiovascular causes might be partially explained by differences in the trial design and eligibility criteria, the systolic blood pressure targets, or the geographic location along with the racial and ethnic background of the trial population.

36. Strengths of the STEP trial include the large sample size, the diverse patient population (ranging from 60 to 80 years of age) with coexisting chronic diseases, the high rate of follow-up, and the use of home blood-pressure monitoring. Given the large population of patients 60 to 80 years of age with hypertension, the trial results could be generalized to and benefit more than 100 million persons in China. The between-group differences in systolic blood pressure were significant, persistent, and consistent across office and home blood-pressure measurements. Home blood pressure monitoring more accurately reflects the long-term fluctuations in blood pressure than office blood-pressure monitoring and facilitates hypertension management for older patients.

37. A limitation of our trial is the inclusion of only Han Chinese persons, which account for more than 90% of the Chinese population. this factor limits the generalizability of our findings.

38. Another limitation is that the Framingham Risk Score was formulated primarily in White populations18 and may overestimate the risk of cardiovascular disease in Chinese adults . Several other issues — such as the effects of intensive blood-pressure control on quality of life, cost effectiveness, and long-term clinical outcomes — could be addressed in future research.

39. Thank you