When the United States Preventive Services Task Force (USPSTF) recently released revised guidelines for initiating statin therapy for preventing major cardiovascular events, it sparked an intense debate on whether the approach was justifiably prudent or unduly conservative. The guidelines proposed the initiation of moderate intensity statin therapy for people between 40-75 years with no prior history of cardiovascular disease but with a 10% or more estimated risk of death, heart attacks, or strokes in the next 10 years if left untreated. Statins control that risk mainly by lowering blood cholesterol (especially its LDL fraction). Their protective role is undisputed in preventing recurrent attacks and delaying death in persons who have already experienced a heart attack or a stroke (secondary prevention). However, there are debates about for whom and when statins should be used to prevent a cardiovascular event among those who haven’t had any as yet (primary prevention).
The recent debate centres around competing guidelines of professional bodies in US. Those proposed earlier by the American College of Cardiology (ACC) and the American Heart Association (AHA) are elaborate in risk assessment and liberal in advising statin use. They recommend a 7.5% risk threshold (for major cardiovascular events in 10 years) and even a 5% risk level in some cases. Both sets of guidelines use the Pooled Cohort Equations (PCE) for future risk prediction. These are derived from long term observational follow-up (cohort) studies of population samples, conducted to track the occurrence of adverse events over time.
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The benefits and risks of statin use are assessed in randomised clinical trials (RCTs) where those on active medication are compared with those who receive a placebo. Impact of treatment is assessed both as Relative Risk Reduction (RRR) and Absolute Risk Reduction (ARR). While ARR measures the difference between the actual event rates observed in the two groups, RRR reports the ratio between the event rates as a percentage. Even when RRR appears impressive, ARR will be less meaningful if the manifest risk is low. Even at an RRR of 25%, numbers needed to treat (NNT) for preventing one event will be far higher if the absolute risk of events is 2% rather than 12%.
Based on results from 23 RCTs and three observational studies, USPSTF recommended statin use in 40–75-year-olds who have a 10% or higher risk of future events and also presently have one of four major cardiovascular risk factors (abnormal blood lipid levels, hypertension, diabetes, smoking). They suggest that statins will not confer substantial benefit in younger people or those with a lower absolute risk. The ACC-AHA guidelines include additional risk predictors (such as coronary artery calcium scores) and risk enhancers (metabolic syndrome, inflammatory disease, family history). They also consider treating younger people at high risk, such as those with familial high cholesterol disease. Many American cardiologists view statins as highly effective agents at any level of increased risk.
Other physicians defend the USPSTF guidelines as being sensible in defining groups which are most likely to benefit from statins while avoiding over-treatment and adverse effects in others.
Concerns have been raised about side effects of statins but USPSTF found no evidence of serious adverse effects. One study (the JUPITER trial) reported a risk of diabetes with rosuvastatin. While RCTs are useful in studying the efficacy of medicines, their side effects are revealed better after their use in a larger number of patients in routine practice. USPSTF recommends initiation with moderate statin doses to avoid serious side effects. A recent study reports that LDL targets can be achieved by a moderate statin dose if combined with ezetimibe. Some US experts argue that it is unwise to defer statin therapy in people younger than 40 and advocate statins if LDL levels are high rather than risk progressive blood vessel damage by waiting for them to cross the 10% risk threshold at 40 years. Others recommend healthy diets, exercise, and smoking cessation to stall progression to high risk in a group where risk is currently low.
The US risk prediction charts are not readily applicable to India, where cardiovascular events occur at a younger age. The first heart attack, on average, occurs a decade earlier than in the US. Diabetes and pre-diabetes are widely prevalent below the age of 40 years. Among blood lipids, US guidelines focus on total LDL levels, while high triglyceride levels and low HDL cholesterol are important risk predictors among Indians. They relate well with the highly atherogenic ‘small dense LDL’ sub-fraction even when total LDL is not high.
We need to develop Indian guidelines based on our own epidemiological data and clinical research. Till then, moderate statin dosage may be initiated in those judged to be at high risk, based on clinical assessment, measured risk factors, and family history. We must advocate healthy diet, age-appropriate level of physical activity, tobacco avoidance, and control of risk factors like hypertension and diabetes to all. While guidelines provide a useful but fixed road map, doctors must be guided by the adaptive GPS of individual risk profiling to decide on a change of course.
The author, a cardiologist and epidemiologist, is president, Public Health Foundation of India (PHFI) Views are personal