Stroke prevention in T2D – REWINDing the clock?

14th March 2020, Dr Chee L Khoo

Despite significant reduction in cardiovascular events over the last 20 years in the general population, patients with diabetes still has 1.5-2 times the risk of cardiovascular events and cardiovascular mortality compared with the general population. It was pretty exciting when two classes of the new anti-diabetic medications have been shown in a number of landmark trials to reduce composite cardiovascular events patients with type 2 diabetes (T2D) and previous cardiovascular disease or patients with T2D with multiple cardiovascular risks.

Remember, the cardiovascular outcome trials (CVOTs) were originally designed to demonstrate the safety of new anti-diabetic drugs following the worries from adverse reports on rosiglitazone (Avandia) and following the surprising results from the ACCORD study which showed increase mortality with intensive glucose lowering in T2D patients with high cardiac risks. To demonstrate cardiovascular safety, all that was needed was for drugs to demonstrate composite major adverse cardiovascular events (MACE) that are not higher than placebo. MACE consisted of non-fatal MI, non-fatal stroke and cardiovascular mortality. Much to our surprise, not only did many of the agents demonstrated cardiovascular safety, some demonstrated cardiovascular benefits. The SGLT2 inhibitors and GLP-1 agonists not only improve glycaemic control, both classes have been shown to improve MACE in patients with T2D and existing cardiovascular disease.

We looked at the 2019 AHA/EASD hyperglycaemia management guidelines couple of months ago here. There were a number of minor yet significant updates from the 2018 guidelines. We highlighted 5 recommendations arising out of the guidelines. Recommendation 1 – T2D with atherosclerotic CV disease (ASCVD) is worth exploring in detail. This recommendation was based on the findings from the REWIND study which published in June 2019. Let’s look at the study in detail and see how it relates to our management of patients with type 2 diabetes in general practice.

Dulaglutide comprises of two GLP-1 molecules linked together and have a half life of 5 days. It is given subcutaneously weekly. Like other GLP-1 agonists, it reduces glucose, blood pressure and body weight. CVOTs from other GLP-1 agonists (shows cardiovascular benefits with reduction in the composite MACE in patients with high cardiovascular risks. The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was designed to assess whether the addition of dulaglutide to the diabetes medication regimen of middle-aged and older people with type 2 diabetes safely reduces the incidence of cardiovascular outcomes compared with placebo.

Patients with T2D aged >50 years old whose HbA1c ≤9.5% on up to two oral antidiabetic agents with or without basal insulin were randomised in a double-blind placebo controlled multi-centre trial. The patients need to have vascular disease (ie, a previous myocardial infarction, ischaemic stroke, revascularisation, hospital admission for unstable angina, or imaging evidence of myocardial ischaemia. Patients > 55 years old had to have myocardial ischaemia, coronary, carotid, or lower extremity artery stenosis exceeding 50%, left ventricular hypertrophy, estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1・73 m2, or albuminuria; and those aged 60 years or older had to have at least two of tobacco use, dyslipidaemia, hypertension, or abdominal obesity. In other words, if you look at the patient mix in this study, you will note that the mix is similar to the patient mix that we see at our practice – some with established cardiovascular disease but many have a few cardiovascular risk factors.

The primary outcome was the occurrence of any component of MACE. The secondary outcomes were a composite of progression of retinopathy, renal disease and hospitalisation for unstable angina.

The results

All up 9901 patients were randomised to either weekly dulaglutide or placebo. Average age of the patients were 66.2 years, average duration of diabetes was 9.5 years. 31.5% of subjects had previous cardiovascular disease and 22% had an eGFR of ≤ 60 mL/min per 1・73 m2. After an average of 5.4 years of follow up, the primary composite MACE occurred in 12.0 % of patients on dulaglutide and 13.4% of patients on placebo (hazard ratio of 0.88, p=0.026). However, when you break down the individual components of the MACE, the hazard ratio (HR) for cardiovascular death was 0.91 (p=0.21) and for non-fatal myocardial infarction was 0.96 (p=0.65) which is not statistically significant. Only the HR for non-fatal stroke of 0.76 (p=0.17 was statistically significant. In other words, much of the composite MACE outcomes came from improvement in non-fatal stroke. See Figure 1.

When the data was sub-analysed, the HR were unchanged whether the subjects had prior cardiovascular disease or not or whether the HbA1c was above 7.2% or below 7.2%. The HR were also unaffected by duration of diabetes, age, sex or BMI.

There was a reduction in the composite microvascular outcomes (HR 0.87) primarily driven by reduction in the composite renal events (HR 0.85). There were no reduction in all-cause mortality, heart failure, revascularisation or hospital admissions. As expected, dulaglutide resulted in lower HbA1c (-0.61%), body weight (-1.46kg), systolic BP (-1.7mmHg), higher heart rate (+1.87 beats per min), lower total cholesterol (-0.07 mmol/L) and lower LDL (-0.05 mmol/L).

In patients with T2D and multiple risk factors, the number to treat (NTT) to prevent one cardiovascular event was 60 but for patients with T2D with known previous cardiovascular disease, the NTT was 18.

In summary

The addition of weekly dulaglutide to existing anti-diabetic agents in patients with T2D with a range of HbA1c can reduced cardiovascular events although most of the benefits were in the reduction of non-fatal strokes. This benefit was seen in both patients with previous cardiovascular events or with multiple cardiovascular risks. Further, dulaglutide can also reduce microvascular events especially renal events. These improvements in macro and microvascular outcomes comes on top of improvement in HbA1c , body weight, systolic BP and lipids.

As the 2019 ADA/EASD hyperglycaemia managmenet guidelines indicated, when managing hyperglycaemia in patients with T2D, one should consider more than just glycaemic control. There are agents which has other benefits in addition to reduction in HbA1c. In CVOTs, both the SGLT2 inhibitors and GLP-1 agonists have been shown to reduce composite MACE. However, much of the benefits in the SGLT2 inhibitors class came from reduction in hospitalisation for heart failure. The REWIND study shows that dulaglutide appears to have more stroke prevention benefits. Both classes appear to show renal benefits.

Reference:

Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled Trial. Lancet 2019; 394: 121–30

PFO Closure

Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012; 366: 991–

A multicenter, randomized, open-label trial of closure with a percutaneous device, as compared with medical therapy alone, in patients between 18 and 60 years of age who presented with a cryptogenic stroke or transient ischemic attack (TIA) and had a patent foramen ovale. The primary end point was a composite of stroke or transient ischemic attack during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years.

Results:

Primary end point was 5.5% in the closure group as compared with 6.8% in the medical-therapy group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.45 to 1.35; P = 0.37)

Conclusion:

“In patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure

with a device did not offer a greater benefit than medical therapy alone for the

prevention of recurrent stroke or TIA”

2 Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017; 377: 1022–

A multicenter, randomised, open-label trial ,randomly assigned patients 18 to 60 years of age who had a patent foramen ovale (PFO) and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group). The primary efficacy end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomisation.

Results:

Recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient years, respectively (hazard ratio 0.55; 0.31 – 0.999; P = 0.046)

Conclusion:

“Among adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up.”

Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013; 368: 1083–

A prospective, multicenter, randomised, event-driven trial, randomly assigned patients to medical therapy alone (anti-platelet or warfarin therapy) or closure of the patent foramen ovale.

Results:

9 patients in the closure group and 16 in the medical-therapy group had a recurrence of stroke (hazard ratio with closure, 0.49; 0.22 – 1.11; P = 0.08). The primary analysis of the intentionto- treat cohort showed a nominal 51% hazard rate reduction with closure, but the reduction did not reach significance.

Conclusions:

” …there was no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischaemic stroke.”

Sondergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017; 377: 1033–

Multinational trial involving patients with a PFO who had had a cryptogenic stroke, randomly assigned patients to undergo PFO closure plus antiplatelet therapy or to receive antiplatelet therapy alone.

Results:

During a median follow-up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23; 0.09 to 0.62; P=0.002).

Conclusions:

“Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation.”

Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017; 377: 1011–

In a multicenter, randomised, open-label trial patients 16-60 years of age who had had a recent stroke attributed to PFO, to transcatheter PFO closure plus long-term antiplatelet therapy, antiplatelet therapy alone or oral anticoagulation.

Results:

No stroke occurred among patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet- only group (hazard ratio, 0.03; 0 to 0.26; P<0.001). Large number of patients discontinued anti-coagulation in the anti-coagulant group and statistical significance was not analysed because the study was not adequately powered to compare outcomes.

Conclusion:

“Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation.”

Lee PH, Song J-K, Kim JS, et al. Cryptogenic stroke and high-risk patent foramen ovale: the DEFENSE-PFO Trial. J Am Coll Cardiol 2018; 71: 2335–

Patients with cryptogenic stroke and high-risk PFO were divided between a transcatheter PFO closure and a medication-only group.

Results:

No events occurred in the PFO closure group. 12.9% of patients in the medication group had an event (p= 0.023).

Conclusion:

“PFO closure in patients with high-risk PFO characteristics resulted in a lower rate of the primary endpoint as well as stroke recurrence”