Ischaemic heart disease treatment perspectives

 

Perspective – medication in acute coronary syndromes.

Many of the study endpoints in ischaemic heart disease studies are so-called composite endpoints, meaning that the statisticians analyse a number derived from a combination of adverse events – e.g. myocardial infarction, stroke, death. For simplicity, the table below looks at mortality alone. For many of these interventions, NNTs look considerably better using combined endpoints.

Intervention	NNT
Aspirin + thrombolytics	20
Aspirin (ISIS-2)	42
Thrombolytics[1]	53
Stopping smoking	67
ACE inhibitors (if LVF)	84
Late beta-blockers Early (< 2 days) nitrates[2]	48 125

[1] Fibrinolytic Therapy Trialists Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994;343:311-22.

[2] Perez MI, Musini VM, Wright JM. Effect of early treatment with anti-hypertensive drugs on short and long-term mortality in patients with an acute cardiovascular event. Cochrane Database of Systematic Reviews 2009 Issue 4 Art No.: CD006743.(*Mortality benefit only. Magnesium, calcium antagonists, early beta-blockers and lignocaine confer no survival benefit. There may be other reasons to use them in individual patients.)

Beta-blockers

The addition of early beta-blockade (first 24 hours) to a treatment regimen that also includes use of streptokinase failed to show benefit, possibly because the smaller benefit of beta-blockers was lost in the larger health gain from use of the streptokinase. In spite of a relatively reputable meta-analysis¹ demonstrating this lack of benefit, there is still a powerful groundswell of opinion in favour of early beta-blockade.

Opinion in favour of early beta-blockers is largely influenced by the ISIS-1 trial² that randomised 8037 patients to intravenous atenolol 5 or 10 mg versus placebo (7990 patients). The trial was done before streptokinase was in routine use, and was unblinded. Early mortality was reduced from 4.57% to 3.89%, giving an ARR of 0.68%, and a NNT of 148 (95% CI 77 – 1996).

The more recent COMMIT trial of 45 852 patients in China³ used metoprolol early (IV then oral) and showed no mortality advantage over placebo; the composite of death, reinfarction or cardiac arrest was also no different. For every 1000 individuals treated, 5 fewer had reinfarction and another 5 fewer had episodes of ventricular fibrillation; this was counterbalanced by 11 more patients developing cardiogenic shock.

Perspective – clopidogrel

Clopidogrel is not particularly impressive as additive therapy over aspirin for the secondary prophylaxis of stroke, but short term use (added to aspirin) is reasonable after myocardial infarction – one month of treatment (75 mg/day) after a STEMI, and three months after a NSTEMI . COMMIT⁴ (< 1 month treatment) and CLARITY⁵ (8 days) provide support for short term use after STEMI. Although CURE (use in NSTEMI) gave clopidogrel for a year, 95% of the clinical event prevention happened within the first three months⁶. CAPRIE⁷ and CHARISMA⁸ showed no clear advantage of using the agent in patients after a stroke, although this information is from subgroups of these trials, which are underpowered for this type of analysis. COMMIT, showing a slightly less than 0.6% mortality advantage (NNT 184, 95%CI 96 to 1924), had more than 45 000 randomised patients. After stent placement, clopidogrel use may also be indicated, with duration depending on the type of stent implanted.

Perspective – heparin

In spite of the number of studies comparing LMW heparin with the ‘gold standard’ of unfractionated heparin as an infusion, there is considerable lack of clarity on optimal dosing with the latter. There have been suggestions that a smaller bolus dose (14 U/kg) may be adequate and could reduce the risk of early excessive anticoagulation⁹. Women and the elderly should probably have infusions running at about 12 U/kg/hr (e.g. 750 U/hr for a 60 kg women) and young males who are diabetics and smokers should run at the higher end of 15 U/kg/hr. It is also not entirely clear if the obese should be dosed according to body weight, with some suggesting a cap at 1000 U/hr.

Heparin after streptokinase

The 2017 network meta-analysis shown below found that adding heparin significantly improved mortality at the cost of doubling major bleeds. However the absolute effect sizes were very small and one should probably take care not to over-interpret this sort of information. 

Perspective – GPIIb/IIIA inhibitors.

Although the South African acute coronary syndrome guidelines¹⁰ recommend the use of these agents in high risk patients where angiography will be delayed, all of these agents (eptifibatide, tirofiban and abciximab) are unrealistically priced for inclusion in public sector formularies outside tertiary centres. .