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1st November 2021
A non-fatal myocardial infarction (MI) does not appear to represent a valid surrogate marker for all-cause and cardiovascular (CV) mortality according to an analysis by a researchers from the Department of Medicine, Washington University, US. Surrogate markers and their endpoints are commonly used in clinical trials but a potential problem is that there needs to be some certainty over whether changes in the surrogate are indicative of changes in the final outcome of interest. There are essentially three criteria which need to be met for a surrogate to be deemed valid: a biologically plausible relationship between the surrogate and the final outcome; a consistent association between surrogate and final outcome and that any treatment effect on the surrogate corresponds to a treatment effect on the final outcome. Although there is an abundance of evidence of the association between a non-fatal MI (NFMI) and both all-cause and CV mortality, there is little objective evidence to support the third criteria.
In trying to establish whether a non-fatal MI is a valid surrogate for both types of mortality in trials, the Washington team searched for all randomised studies that considered the treatment or prevention of coronary artery disease and reported a non-fatal MI as an outcome. The inclusion criteria was set as only randomised controlled trials with at least 1,000 patients and 24 months of follow-up. Trial level correlation between NFMI and all-cause and CV mortality was assessed for surrogacy using the coefficient of determination, R-squared, by plotting the individual trial outcome (in this case mortality) against NFMI. The R-squared value corresponds to the explained variation (or association) between these two measures and varies from 0 (no surrogacy) to 1 (perfect surrogacy). The threshold for validating NFMI as a surrogate for all-cause and CV mortality was set at 0.80.
Findings
A total of 144 randomised trials with 5,726,395 patients were included in analysis. In the pooled analysis of these trials, the value of R-squared for all-cause mortality was 0.02 (95% CI 0.0 – 0.08) and 0.11 (95% CI 0.02 – 0.27) for CV mortality. This lack of surrogacy was evident in trials of both primary, secondary and mixed primary/secondary prevention studies. Furthermore, the duration of follow-up had no impact on the association. For example, R-squared was not a surrogate for trials lasting from 2 to 3.9 years (R-squared = 0.004) or even trials with a follow-up of 6 or more years (R-squared = 0.06).
Commenting on their findings, the authors noted that while it is generally assumed that an intervention to reduce NFMI would also reduce all-cause and CV mortality, the results implied that any treatment or intervention designed to reduce a NFMI cannot be assumed to also reduce either all-cause or CV mortality. They also noted that there was a high degree of heterogeneity for the included trials and whilst this is generally considered to be a disadvantage, it actually becomes an advantage for the present analysis as it allows for subgroup analyses to determine if surrogacy exists.
They concluded that while NFMI is not a validated surrogate endpoint for mortality in trials, it’s inclusion may be justified due to the relationship between impaired quality of life and health-care related costs.
Citation
O’Fee K et al. Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality in Treatment or Prevention of Coronary Artery Disease. A Meta-analysis of Randomized Clinical Trials. JAMA Int Med 2021
9th September 2021
A haemorrhagic stroke is due to intra-cerebral haemorrhage (ICH) and one review estimated a 1-year survival of 46% and a 5-year survival of 29%. Moreover, even among survivors, there is a risk of not only a further stroke, but other serious cardiovascular events such as myocardial infarctions. While there is clearly an increased risk of future cardiovascular events after a haemorrhagic stroke, there remains some uncertainty over the value of post-stroke anti-platelet therapy. Part of the reason why clinicians are reluctant to continue with anti-platelet therapy as a secondary preventative measure, is the increased risk of a further stroke, particularly with drugs such as aspirin.
In an effort to provide some much needed clarity over whether or not it was safe to continue with anti-platelet therapy in those who suffered a haemorrhagic stroke, a team from the Centre for Clinical Brain Sciences, University of Edinburgh, UK, undertook the Restart or stop Antithrombotics Randomised Trial (RESTART). The trial included patients who had suffered an ICH while taking anti-platelet therapy (aspirin, clopidogrel and dypridamole) but then discontinued their drug. For the purposes of the trial patients were randomised to either re-start an anti-platelet or avoid further use. After a median follow-up period of 2 years, there was a slight, non-significant (p = 0.06) decreased risk of recurrent stroke among those taking anti-platelet drugs. The same group have now released findings from a follow-up study of those involved in the original trial. For the follow-up study, the primary outcome was fatal or non-fatal radiologically or pathologically proven recurrent symptomatic ICH. The secondary outcomes included major haemorrhagic events and major occlusive vascular events.
Findings
In the original RESTART trial, 537 patients with a median age of 76 years (67% male) were randomised to restart (268) or avoid (269) anti-platelet therapy, a median of 76 days after the onset of their stroke. For the follow-up which lasted a median of 3 years (i.e., 5 years from the original trial), 562 of those from RESTART consented to continue and were randomised as before to re-start anti-platelet therapy (268) or avoid it (268). The primary outcome occurred in 8.2% of those taking an anti-platelet and 9.3% without treatment (adjusted hazard ratio, aHR = 0.87, 95% CI 0.49–1.55, p = 0.64). For the secondary outcomes there was also no significant difference (aHR = 0.79, 95% CI 0.58–1.08, p = 0.14).
These findings provide physicians with some reassurance about the use of antiplatelet therapy after ICH if indicated for secondary prevention of major vascular events.
Citation
Salman RA et al. Effects of Anti-platelet Therapy After Stroke Caused by Intracerebral Hemorrhage. Extended Follow-up of the RESTART Randomized Clinical Trial. JAMA Neurol 2021.
6th September 2021
There are two types of stroke: ischaemic (caused by a clot) and haemorrhagic (caused by a bleed) and the main risk factors for a stroke include hypertension, coronary artery disease, diabetes and obesity. The main factor responsible for strokes is hypertension and it has been estimated that, world-wide, a raised blood pressure, accounts for 54% of all strokes. Moreover, evidence suggests that a reduction of salt intake can reduce blood pressure, leading to a decrease in the risk of strokes. The use of salt substitutes, in which sodium is replaced by potassium, can also lower blood pressure, although the evidence for a beneficial effect on cardiovascular disease and mortality is sparse.
With an absence of randomised trial data examining the impact of salt substitution on cardiovascular outcomes, a team led by researchers from the George Institute for Global Health, Sydney, Australia, established the Salt Substitute and Stroke Study (SSaSS) in 600 rural villages in China. The team enrolled adults with a history of stroke or those who were 60 years of age and older and with poorly controlled blood pressure. This was defined as a systolic > 140mmHg if receiving treatment or > 160mmHg if not on treatment. Individuals were then randomised to receive, free-of-charge, salt substitutes, which contained 25% potassium chloride and asked to use this instead of regular salt for cooking, seasoning food etc. The primary outcome was stroke and secondary outcomes were major cardiovascular events, comprising a composite of non-fatal stroke, non-fatal acute coronary syndrome or death from vascular causes. The main safety outcome was clinical hyperkalaemia and in order to track electrolyte levels, every 12 months, a subgroup of participants provided 24-hour urinary electrolyte excretion.
Findings
A total of 20,995 individuals with a mean age of 65.4 years (49.5% female) were enrolled and randomised to either arm and followed up for 4.74 years. Overall, 72.6% of participants had a history of stroke, 88.4% a history of hypertension. Among those with hypertension, 79.3% were prescribed at least one anti-hypertensive and the mean sample blood pressure was 154/89.
In participants using salt substitutes, the rate of strokes was lower (rate ratio, RR = 0.86, 95% CI 0.77–0.96, p = 0.006) compared to regular salt users. In addition, both the rate of major cardiovascular events (RR = 0.87) and death (RR = 0.88) were significantly lower in the salt substitute group. Analysis of electrolyte samples during follow-up, also showed that sodium excretion was lower in those using salt substitutes. In terms of safety, there was no significant difference in the level of hyperkalaemia (p = 0.76).
The authors concluded that the use of salt substitutes in those with both hypertension and a prior stroke led to a significant reduction in not only future strokes but also major cardiovascular outcomes.
Citation
Neal B et al. Effect of Salt Substitution on Cardiovascular Events and Death. N Engl J Med 2021
3rd September 2021
Intensive blood pressure control in elderly Chinese patients has been found to reduce the incidence of adverse cardiovascular outcomes.
High blood pressure is an important risk factor for both cardiovascular and chronic kidney disease. As a result, blood pressure treatment guidelines have made recommendations, particularly for target systolic blood pressure values.
There is evidence that lowering this component reduces the risk of cardiovascular disease and all-cause mortality and the current systolic blood pressure target set by the European Society of Cardiology is 130 to 139 mmHg.
#While lowering systolic pressure further to under 120 mmHg in those aged 75 years and older, reduced the incidence of fatal and non-fatal major cardiovascular events, other data has found an increased mortality risk among the elderly.
Given these ambiguities, a Chinese team from the Hypertension Centre, FuWai Hospital, Peking, China, performed a randomised, controlled trial, in hypertensive patients aged 60 to 80 years of age.
They included patients with a baseline systolic pressure of between 140 and 190 mmHg for at least three months prior to the study.
The study examined the outcomes associated with reducing systolic blood pressure to a target of 110 to less than 130 mmHg (the intensive treatment) or a target of between 130 and less than 150 mmHg (standard treatment).
All patients were provided with a home blood pressure monitoring device and were required to provide readings at least weekly during the follow-up period.
The primary outcome of interest was a composite of several adverse cardiovascular events including stroke, acute coronary syndrome and hospitalisation for unstable angina, atrial fibrillation and death from cardiovascular causes.
A total of 8511 patients were randomised to either arm with a mean age of 66.2 years (46.9% male) and a mean systolic blood pressure of 146.1 and a diastolic of 82.7 mmHg.
During a median follow-up of 3.34 years, the primary outcome occurred in 3.5% of those in the intensive blood pressure arm and 4.6% in the standard arm (hazard ratio, HR = 0.74, 95% CI 0.60 – 0.92, p = 0.007).
Furthermore, the individual components of the primary outcome were also significantly improved in the intensive arm.
For example, the hazard ratio for stroke was 0.67 (95% CI 0.47 – 0.97), acute coronary syndrome (HR = 0.67) and although death from any cardiovascular cause was reduced, this was not significant (HR = 0.72, 95% CI 0.39 – 1.32).
There were also no differences in safety outcomes such as hypotension, dizziness, syncope or fracture and for renal outcomes.
The authors concluded that intensive blood pressure lowering among elderly patients was associated with a reduced risk of adverse cardiovascular outcomes.
However, a recognised limitation was that it was undertaken in a Chinese population which could reduce the generalisability of their findings and that the study excluded patients with a history of stroke.
Citation
Zhang W et al. Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension. New Eng J Med 2021.
15th July 2021
The omega-3 fish oils eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) appear, at least from some trials, to reduce adverse cardiovascular events although the evidence is still inconclusive. The purported mechanisms through which omega-3 fish oils might reduce cardiovascular events include the ability to lower triglycerides, their cell membrane stabilising effects, together with a collective antithrombotic, anti-inflammatory and anti-arrhythmic effect. However, trials published in 2018 produced divergent results; the ASCEND trial showed no benefit in diabetics without cardiovascular disease. In contrast, the REDUCE-IT trial found a 25% reduction in the primary composite efficacy endpoint of cardiovascular death, non-fatal MI, stroke and coronary revascularisation, with a highly purified form of EPA in those with established cardiovascular disease. In fact, other evidence shows that EPA alone led to a 19% reduction in major coronary events in patients with hypercholesterolaemia.
In light of this possible heterogeneity with the two omega-3 fish oils, a team from the Department of Medicine, West Virginia University, US, undertook a meta-analysis of the effects of omega-3 fatty acids on cardiovascular outcomes. The team included only randomised controlled trials in adults that compared omega-3 fish oil intake (EPA or EPA and DHA) to placebo, trials with at least 12 months follow-up and where the cardiovascular outcomes of interest were recorded. There were a number of specified outcomes including cardiovascular mortality, all-cause mortality, non-fatal MI and haemorrhagic stroke. The safety endpoints included atrial fibrillation (AF), major and minor bleeding.
Findings
A total of 38 trials including 149,051 patients were included in the final analysis. There were 4 trials with EPA alone with the remainder comparing both omega-3 fish oils against placebo and 22 trials focused on primary prevention. The dose of omega-3 fish oils ranged from 0.4g/day to 5.5g/day and the median duration of follow-up in trials was 2 years. Overall, the use of EPA and DHA was associated with a small, but statistically significant reduction in cardiovascular mortality (relative risk, RR = 0.93, 95% CL 0.88 – 0.98, p = 0.01), but not all-cause mortality (RR = 0.97, 95% CL 0.93 – 1.02, p = 0.27). Interestingly, the use of EPA alone, led to a greater reduction in cardiovascular mortality that the combination of the two (RR = 0.82 vs 0.94, EPA alone vs EPA & DHA). Again, mono-therapy with EPA showed a higher risk reduction in non-fatal MI (RR = 0.72 vs 0.92, EPA alone vs EPA & DHA). Despite these additional benefits, use of EPA alone resulted in a higher risk of total bleeding (RR = 1.49) and development of AF (RR = 1.35) although the authors cautioned that the certainty of this evidence was of low quality.
They concluded that while the available evidence does show that the omega-3 fish oils are associate with a small, but significant cardiovascular benefit, there seems to be a slight advantage to using EPA alone but called for further research to examine this observed effect in more detail.
Citation
Khan SU et al. Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis. EClinical Med 2021
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