Optimal Medical Therapy

A meta-analysis of 18 studies confirms that differences in risk-factor burdens in middle age translate into significant differences in lifetime cardiovascular disease risk.  The new results from the Cardiovascular Lifetime Risk Pooling Project, published in the January 26, 2012 issue of the New England Journal of Medicine, show that risk in people in their 40s or 50s with one or two risk factors such as hypertension or high cholesterol ramps up sharply over their lifetime.

I find many “healthy” people fail to take care of their conventional cardiovascular risks because of a low short-term (10 year) risk for vascular events yet their life-time risk is very high.  There’s therefore a disconnect between the short-term risk information that we routinely calculate and long-term risks that are dramatically higher.

This isn’t necessarily news, but this is a new way to look at what you should be doing if I can tell you that, sure your 10-year risk may be low, but based on your profile right now, your lifetime risk might be 50% or more of having a major heart attack or stroke before you die. . . . I hope that’s a little more of a motivating message.

The study analyzed 18 cohort studies with 257 384 patients, including black and white men and women across a 50-year range of birth cohorts. The studies measured important cardiovascular risk factors at ages 45, 55, 65, and 75. The risk factors measured include smoking, cholesterol levels, diabetes, and blood pressure.

Calculation of lifetime risks of cardiovascular events shows that the presence of even one risk factor in middle age can dramatically increase one’s lifetime risk of cardiovascular disease compared with no risk factors, and the risk goes up with each additional risk factor.

Across the whole meta-analysis, participants with no risk factors at age 55 (total cholesterol level: < 4.5 mmol/l; blood pressure: <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking; nondiabetic) had drastically better odds of avoiding death from cardiovascular disease through the age of 80 than participants with two or more major risk factors (4.7% vs 29.6% among men and 6.4% vs 20.5% among women).

People with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs 37.5% among men, <1% vs 18.3% among women) and fatal or nonfatal stroke (2.3% vs 8.3% among men, 5.3% vs 10.7% among women), compared with those with two or more risk factors.

The lifetime risk of death from cardiovascular disease and coronary heart disease or of nonfatal myocardial infarction were generally about twice as high among men than among women, but the lifetime risks of fatal and nonfatal stroke were similar for men and women.

Now Is the Time to Address Risk Factors:

If we can get our young adults living healthier lifestyles and more of them into middle age with optimum [risk-factor] levels, that would be fabulous news, but if you are middle-aged and you do have a risk factor or two or more, it’s really time to address those risks.

Published in SCIENCE (2002) using a combination of balanced lifestyle intervention and modern pharmacotherapy; data suggest that world-wide we could largely eliminate the 4 major disease processes if we can enable adults to avoid risk factors in the first place. Vascular & heart disease IS a preventable disease.

Modifying the major risks for vascular disease:

For many years cardiologists have known that small reductions in BP and Cholesterol confer over many years substantial reduction in cardiovascular risk.

What is less well-known is what “aggressive multiple risk reduction” will achieve over many decades of life starting in early or mid-life.

On really meticulous lifestyle with daily moderate intensity conditioning exercise; optimal dietary intervention; good sleep hygiene – what if we could optimise BMI < 25; lower LDL < 1.8; keep BP 120/80; reduce us-CRP < 1.0; maintain normal glycaemic control (with no glucose intolerance or Insulin resistance) and maintain a resting heart rate < 70 bpm LIFELONG?

We really do understand the pathological process of cardiovascular disease:

The pathophysiology of ageing of our cardiovascular system is complicated with complex risk factor intervention.  As the previous BLOG indicated, atherosclerosis is initiated and driven by a cascade of inflammatory mediators and players with athero thrombosis (increased coagulation) featuring prominently in the progression and complication of the atherosclerotic plaque. We are BLESSED in Cardiology to have a 30 year history of evidence-based; randomised; placebo-designed; double blinded trials from ALL 4 corners of the earth which have looked at various interventions in reducing the various risk factors and what happens to objective “hard end-points” of morbidity and mortality over time.  We have extensive modern pharmacotherapy with excellent RISK verses BENEFIT to target each of the individual risks and specifically to prevent plaque formation; regress plaque and stabilise plaque.

Management of systemic hypertension:

There is irrefutable evidence-based data to support maintenance of low risk healthy BP as you age to ~ 120/80.

The goal is to prevent the sinister end-organ complications of hypertension including acceleration of atherosclerosis; hypertensive heart damage; hypertensive central nervous system damage; renal damage and ocular damage.

Any individual with hypertensive target organ damage risk stratifies into a much poorer prognosis and warrants meticulous blood pressure control with modern blood pressure agents that interfere with the neurohormonal dysfunction common to hypertension.  As indicated in the previous blog there is considerable evidence to suggest the Angiotensin Converting Enzyme Inhibitors (ACE-I) and the Angiotenisn Receptor Blockers (ARB) directly influence the progression and complication of the atherosclerosis process and treatment with these agents reduce all hard vascular end-points.

Management of dyslipidaemia:

Three decades of research and development and masses of clinical trials have contributed to the understanding that we can prevent the development of atherosclerosis; prevent the progression and complication of atherosclerosis and actually reverse atherosclerosis with plaque regression.  To achieve this it appears you do not want a LDL cholesterol too much above 1.8 mmol/l and HDL cholesterol needs to be > 1.2 mmol/l.

Cholesterol reduction in 2012:

Since the publication of the first cholesterol lowering trials in 1994, subsequent trials have confirmed the beneficial effects and safety profile of STATINS to lower cholesterol.  By pooling data from many of the many published international trials, it is possible to analyze both the positive and negative effects of the statins, based on larger numbers of observations, and begin to tackle some of the crucial issues such as: will statins be beneficial in all people including the very old, in women, in people with diabetes or in people with no cardiovascular disease (primary prevention of cardiovascular disease)? Can we be sure that statins do not cause harm, such as cancer, liver damage, muscle injury or hemorrhagic stroke?

The Cholesterol Treatment Trialists has published results from a meta-analysis of 14 randomized clinical trials.   The primary meta-analysis measured the effects on clinical outcomes (all-cause mortality, coronary heart disease [CHD] mortality and non-CHD mortality) in each trial according to the absolute low-density lipoprotein (LDL) cholesterol difference at the end of the first year of follow-up. The results were reported as effects per 1.0 mmol/l LDL reduction. Secondary analyses looked at the effects of Statins therapy on CHD death and major coronary events (MCE) in specified subgroups. Data were obtained on 90,056 individuals, 47% of whom had pre-existing CHD. Twenty four per cent of the participants were women, 21% had a history of diabetes, and 55% had hypertension. The average difference in LDL cholesterol levels at 1 year was relatively small at 1.09 mmol/l, and the mean follow-up was 4.7 years (range, 2–6 years).

Despite this small LDL reduction the primary meta-analysis revealed a 12% reduction in all-cause mortality per 1.0 mmol/l reduction in LDL cholesterol, which was largely attributable to a 19% relative reduction in CHD deaths. This reduction was similar in all subgroups including the elderly (>75 years of age), women, treated hypertensive patients with a diastolic blood pressure >90 mmHg, people with a history of diabetes (including those without vascular disease), and those with pre-treatment LDL cholesterol levels <2.60 mmol/l. There was a highly significant 23% relative reduction in the incidence of first MCE per 1.0 mmol/l reduction in LDL cholesterol, including a 26% reduction in non-fatal myocardial infarction. A significant trend toward a greater relative benefit with greater reductions in LDL cholesterol concentrations was also noted.

Coronary bypass operations were reduced by 24% per 1.0 mmol/l reduction in LDL cholesterol levels and a significant 17% relative reduction in the incidence of first stroke was noted. Once again, there was a significant trend towards greater relative reductions in stroke, associated with greater mean absolute LDL cholesterol reductions. The overall reduction in strokes largely reflected a 19% relative reduction in non-hemorrhagic strokes, with no difference in hemorrhagic strokes. The 5-year results revealed a relative reduction of major vascular events of 21% per 1.0 mmol/l reduction in LDL cholesterol concentrations. Similar reductions were seen in MCEs, coronary revascularizations, and strokes.

An analysis of safety issues showed neither an increased risk in first incident cancers nor any evidence of an excess incidence of cancer with increasing duration of treatment. The 5-year risk of muscles damage (rhabdomyolysis) was small and there was no appreciable difference in liver problems on statins as compared to Placebo.

In more recent years the advent of potent and more effective statins (these can reduce LDL by 2-5 mmol/l) have changed the landscape of preventing vascular disease further.  The results of the JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin) trial from November 2008 add a formidable amount of information about the beneficial effects of statins.

This study screened almost 90,000 healthy volunteers aged 50 years or more (in the case of men) or 60 years or more (women). One in five (17,802) of those screened were included in the trial. Normally, the participants would not have qualified for statin therapy; they had no history of cardiovascular disease, and their low-density lipoprotein cholesterol (LDL-cholesterol) levels were below the usual threshold for treatment of 3.33 mmol/L.  The trialists hypothesized that high-sensitivity C-reactive protein (hs-CRP) is helpful in identifying individuals at high risk, and they restricted the selection of participants to those with hs-CRP levels of 2.0 mg/dl or more. Furthermore, given that statins reduce high levels of hs-CRP, the investigators expected to see a bonus of reduced inflammation through hs-CRP-reduction.

When the trial was prematurely discontinued, after 1.9 years, Rosuvastatin (Crestor) 20 mg daily had reduced LDL-cholesterol levels by about 50% in comparison with placebo, and the results were impressive: in the rosuvastatin group, the relative risk for the primary endpoint of cardiovascular events was reduced by 44%. If this method of selecting candidates for statin therapy was to be transferred to clinical practice, we might see a substantial increase in the proportion of statin-users in the middle-aged and elderly population.

Given that the median follow-up time was only 1.9 years, the absolute reduction in risk over a longer period of, say, 5 years has to be estimated. The investigators found it plausible that the number of people needed to be treated to prevent one primary endpoint was 25. This is well in the range of other preventive medical therapies in frequent use today.

Of importance the reduction in risk was remarkably consistent across all sub groups including males; females; smokers; non-smokers etc.

Of great relevance was the data to show the reduced risk if both LDL was reduced ~ 1.8 and us-CRP was reduced < 1.0 conferring >70% risk reduction.

The results of the JUPITER trial are likely to expand the target population eligible for statin therapy, but healthcare providers face a tough question: can we afford it?  First, the analysis reinforces the findings of the individual trials showing that statins are very efficacious and safe. The results also strongly support the idea that most patients at risk of CVD benefit from treatment. This includes the elderly, women, and specified subgroups. The beneficial effect appears linked to the degree of LDL cholesterol lowering, a finding of utmost importance for the management of people at risk. If we could lower LDL cholesterol by 3.0-4.0 mmol/l, we would theoretically reduce major cardiovascular events by as much as 60-80%. If we then consider that the data presented reflect only a short period of time and were focused on first events with significant results, we must contemplate the effects we may achieve over an extended lifelong period of treatment.

The possible benefits, however, require that patients are indeed offered a Statin and then stay on their therapy for life. Unfortunately, ample evidence points to poor compliance, both regarding the number of patients treated and the unsatisfactory management of their LDL cholesterol levels.

The mechanism for improved outcome from Statins appears to be multiple including plaque stabilisation with reduced fissuring and rupture; plaque compaction and regression and interference with the entire cascade of cytokine production and inflammation.  The stability of the atherosclerotic plaque related to a much more dense fibrous capsule separating the contents of the plaque from the blood; decrease inflammatory content of the plaque primarily through lowering oxidised LDL.  Plaque compaction and plaque regression is evident on INTRAVASCULAR ULTRASOUND (IVUS) – left picture with LDL maintained at 1.6-1.8 mmol/l over 18-24 months.

The whole gambit:

Anti atherosclerosis therapy may involve multiple agents to influence the pathophysiology of the events causing atherosclerosis.

Having practised cardiology over the past 20 years; having studied intensely the evolution of vascular biology and the pathophysiology of atherosclerosis and more importantly having seen what aggressive risk reduction does in primary and secondary clinical scenarios I am absolutely convinced if we mange risk aggressively we can abrogate this sinister disease.

Say No.

Yes to healthy ageing.

Hope this helps.

Cardiologydoc