By Dr. Tony Neaverson

INTERNAL MEDICINE SOCIETY AUSTRALIA & NEW ZEALAND – ANNUAL SCIENTIFIC MEETING, LORNE , VICTORIA NOVEMBER 11-13TH 2011

THE CONUNDRUM
On the morning of October 11th 1984 Kevin Petterson, aged fifty years with a provisional diagnosis of ischaemic pain,    became the first person in a peripheral Sydney Hospital to undertake a modified Bruce Protocol in an attempt to prove his provisional diagnosis.
At that time coronary angiography was in its infancy and in an attempt to identify those post infarct patients likely to benefit from an angiogram all post infarct patients were asked to undertake a pre discharge eight minute stress test to five mets of activity irrespective of their admission Killip Score.
Those able to complete this study without heart rate greater than 130bpm, 10-15mm Hg fall in systolic BP, ST changes ± ischaemia pain or  exhaustion had been shown to have a good twelve month prognosis which we later showed extended to five years.
The remaining symptomatic patients could be considered for intervention.
It soon became evident that some form of out patient care would benefit many patients in their on going medical management and on January 22nd 1985 the first patient, Robert Myall, was admitted into a dedicated out patient programme of eighteen half hour exercise sessions over a six week period.
All patients had pre and post programme stress tests in order to obtain their individual exercise prescription and identify changes after training together with a lipid reviews.
The exercise format was of high intensity anaerobic interval training with endurance phases of three to five minutes with commencing heart rate targets of 75-85% of attained rate and increasing both in duration and work load at each attendance.
This format (Neocardial™ Exercise) has continued unchanged since its inception for the last ten years in Noosa.
In 1992 Shaw and Amin2 reported the effect of low HDL levels on restenosis rates in patients post balloon angioplasty: those with HDL < 1mmol/L had a 64% rate at two months whilst those with HDL > 1mmol/L 17% – six month overall rates were of the order of 30%. These early stenotic lesions occurred within two months of the procedure and were of greater severity than traditional lesions. High and prolonged levels of exercise have been shown to increase HDL levels.
Figure 1 demonstrates the mean and standard deviation increase of HDL in patients with initial low levels (< 1.0mmol/L) after six weeks of Neocardial™ training covering the years 1984-2011. Years including more than eighteen patients reached significant increases in HDL. Percentage increases in HDL levels are shown in the graph.

Over the years one of us (TN) became aware that , for some reason, the significant elevation of HDL which had occurred prior to 2003 was no longer apparent in the years 2003-2007 despite the fact that the identical exercise prescription was in place.
Over the seven years 1985-1995 the average percentage rise was 19% (range 11-34%) whilst from 2001-2008 this average had fallen to 9% (range 1-18%).

THE HYPOTHESES:

1. Lipid Lowering

One initial hypothesis was that this reduction may have been associated with the introduction of lipid lowering therapy with statins which had (due to relaxation of PBAC requirements) become more readily available.
Whilst tightly controlled clinical trials demonstrate significant reduction of LDL with the newer agents (and higher  dosages of established therapies) in the workplace compliance poses a significant problem with fewer patients reaching target lipid levels.

Recently Barter and his colleagues3 undertook a Meta analysis on the effect of treatment with three statins rosuvastatin, simvastatin and atorvastatin on HDL level and noted -

“The HDL raising ability of rosuvastatin, and simvastatin was comparable, with both being superior to atorvastatin. Increases in HDL –C were positively related to statin dosage with rosuvastatin and simvastatin but inversely related to dose with atorvastatin”

Table demonstrates the clinical importance of increasing the HDL levels

Statins are not without significant side effects which appear to be dose related. In addition to myopathy and potentially lethal rhabdomyolysis, abnormal liver function and interference with muscle metabolism (associated with elevated CK levels) have been reported.
There is now good evidence that, particularly in the overweight and obese individual, statin therapy may interfere with the patient gaining maximum benefit from physical activity.

2. Impaired Physical Improvement

The MHVO2/VO2 ratio is an indication of physical fitness. MHVO2 is derived from a nomogram based on the Maximum Pressure Rate Product and relates to the oxygen consumption of 100 Gm myocardial tissue. The VO2 is derived from the number of completed mets the during his treadmill test. The lower this ratio the fitter the individual e g <10 very fit > 30 grossly unfit.
Recently there has been a tradition to maximise atorvastatin therapy to 80mg daily.
Figure 2 illustrates the significant difference in MHVO2/VO2 ratio in patients not on statin therapy versus those on Atorvastatin 80mg after eighteen sessions of exercise.
Those on the high dose of atorvastatin failed to improve their physical fitness- at lower doses smaller reductions are noted. This effect is not apparent with other statin treatments.
Inability to improve physical fitness will also limit ability to loose weight.
Figure 3 illustrates the difference in Body Mass Index between patients not on statins and those on 80mg atorvastatin. Once again there is a significant  difference.

3. Population Characteristics

Table 1 compares the characteristics of the Sydney and Noosa Group of patients pre and post programme.

Clearly one significant difference is the differences between the patient uptake of primary or secondary prevention.
Additionally independent t-test of most variables in Sydney v Noosa Format found significant differences in age, blood pressures, fitness ratio, mean BMI, and triglycerides and pre and post LDL, LDL/HDL ratio.
When Noosa Patients on statins were excluded the following variables lost significance: Mean resting SBP, and pre MHVO2/VO2 ratio. The following gained significance pre and post BMI.
Indicating that the Sydney population was significantly sicker and questioning the effect of lipid lowering medication.

DISCUSSION

Since their introduction use of statin therapy worldwide has escalated based essentially on their effect of lowering LDL levels and the beneficial effects predominantly in tightly controlled secondary prevention studies.
Antagonists have variously claimed patient selection and exclusion criteria, lower levels of patient compliance (65% at two years in Australia4) and occasional troublesome side effects as negative features of statin value. Notwithstanding there have been many supporters who have called for higher dosages and reduced target levels resulting in an Australian increase of serum lipid lowering agents over the last decade of 1218% an annual costs approaching $2billion.
A decade ago similar calls were made in the USA when, after new guidelines, suggested that 13-36 million of that population, most of whom did not have, but were estimated to be at moderately elevated risk of developing coronary heart disease would benefit.
A similar call was made by Chen et al5 to which one of us (TN) felt compelled to submit a contrary view for publication which contained the following statement….

“In a letter announcing the PBAC listing of ezetrol the company concerned acknowledged that 50% of patient taking a simvastatin failed to attain target levels arguing that if the PBAC allowed the combination of simvastatin and exetimibe onto the list this deficiency would be overcome….. despite the fact that four major trials on this proposition remain unreported their argument was found acceptable and resulted in a further increase in pharmaceutical costs the combinations retailing at $132 and $159 per month”.

In rejecting my submission one of the referees expressed the opinion to the effect that clinical trials were not required as further therapeutic lowering of LDL had been demonstrated.

Subsequent clinical studies of Ezetimibe added to statin reduced HDL-C by an additional 17% without added benefit in atheromatous regression as measured by carotid intima-media thickness (CIMT).
In June 2011 the FDA issued new labelling changes for simvastatin 80mg and in reviewing all available data made the following statements in part:
“ All showed that patients taking simvastatin 80mg daily had an increased risk of muscle injury compared to patients taking lower doses of simvastatin or other statin drugs……..the highest dose should no longer
be prescribed for new patients………incidence of myopathy is higher in patients of Chinese descent who should not receive simvastatin 80mg”
“……. Until further data on the efficacy of ezetimibe becomes available, the use of ezetimibe in lipid management therapies warrants careful consideration”6
Despite aggressive LDL reduction with statin therapy the five year risk of a cardiovascular event in those receiving statins was 14% compared to 18% in those receiving placebo.
Barter et al7 showed that in patients with LDL below 70mg/dl (1.8mmol/L) in the highest quintile of HDL-C levels were at a significantly lower risk for major cardiac events than those in the lowest HDL quintile (<0.03).

SUMMARY

• Whilst increasing doses of statin therapy may be associated with further lowering in LDL C such changes may not be associated with improved overall care of the patient.
• With increasing doses of atorvastatin elevation of HDL is significantly impaired. Likewise high doses of simvastatin (80mg) are best avoided due to muscle injury.
• Patients taking high doses of atorvastatin (80mg) appear unable to gain the traditional benefits of improved fitness and weight loss from physical training.
• The clinical benefit of high doses of statins is questionable and warrants further in depth analysis which is being undertaken.

References:
1 Neaverson MA, “ The benefit of predischarge stress testing of all post infarct patients irrespective of their clinical  picture” Fourth World Congress Cardiac Rehabilitation, Bordeaux, June 1993.
2 Shaw and Amin “Restenosis after elective balloon angioplasty” Circulation 1992;85:1279.
3 Phillip J Barter, Gunnar Brandrup-Wognsen, Mike J Palmer, Stephen J Nicholls “Effects of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database” Journal Lipid Research 2010;51:1546-1553.
4 Susan Senes “ Medicines for cardiovascular health:are the used appropriately?” May 2007 AIHW Canberra).
5 Lei Chen et al “How do Australian guidelines for lipid lowering perform in Practice:” Med J Aust 2008;189: 319-322. 6 Ujjaina Khanderia et al “ The Ezetimibe Controversy” Ther Adv Cardiovasc Dis 2011;5(4):199-208.
7 Barter P, et al “HDL cholesterol, very low levels of LDL, and cardiovascular events” N Engl J Med 2007;357:1301-1310.

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Improvement in Risk Profile of those with a prior heart operation?

Physical improvements in those with a prior heart operation

• Improvement in fitness ratio of 23% (p<0.0001)
• Highly significant improvements in Body Mass Index and weight
• Highly significant improvement in cardiorespiratory function at very light work (11%), light work (12%) and moderate (23%) levels of activity
• Significant improvements in systolic and diastolic blood pressure of 5-10%

• Six-weeks of interval training also had a positive effect on levels of the “good” cholesterol: HDL
• Mean levels were raised significantly (p=0.01) across all patients, offering an increased protective effect against coronary artery disease

Added benefits for those with low HDL Cholesterol
Those beginning the programme with low levels of HDL cholesterol (less than 1mMol/L) are at increased coronary risk however they attain even greater benefits from the exercise with statistically significant (p<0.0001) increases in this good cholesterol, protective against coronary artery disease.

Risk reduction in those with a prior heart attack and low HDL

• The Framingham Risk analysis is a measure of cardiac risk which takes into account several factors including age, sex, cholesterol, blood pressure, weight and smoking habits
• In patients who have suffered a heart attack and have low levels of HDL cholesterol a significant reduction in 5 year Framingham risk occurs with the program

Risk reduction in those with ischemia and low HDL

• The Framingham Risk analysis is a measure of cardiac risk which takes into account several factors including age, sex, cholesterol, blood pressure, weight and smoking habits
• In patients who have angina/ischemia and low levels of HDL cholesterol a significant reduction in 5 year Framingham risk occurs with the program

The Harmful Type B LDL Particle
Bad cholesterol, LDL, actually comes in various sizes. It is only the small and dense Type B particles that are able to pass through holes in the capillaries used for nutrient and oxygen transfer and lay down plaque in the coronary arteries. The smaller your particles the larger the risk.

• Our research has demonstrated a correlation between LDL particle size and the triglyceride/HDL ratio.
• If a person has a ratio greater than 2, 100% of their LDL particles are the harmful Type B, placing them at greater risk of heart disease and stroke. About 1/3 of all Australians fall into this group.
• By decreasing the T/HDL ratio, the amount of small dense particles can be reduced thereby reducing the patient’s risk.

Reducing the T/HDL Ratio
Using exercise and life-style change alone we have significantly reduced this ratio by 16%, meaning that by the end of six weeks the average value for T/HDL is less than 2.0

• Using exercise and life-style change alone we have significantly reduced this ratio by 16%, meaning that by the end of six weeks the average value for T/HDL is less than 2.0

Results in those aged 70 years+

• Similar signifiacnt improvements in fitness (MHVO2/VO2) of 28%
• Similar significant improvements in cardiorespiratory function up to 4 METS of activity (light work)
• Similar signifiacnt improvements in both systolic (10mmHg) and diastolic blood pressure (5mmHg)

Greater improvements in terms of weight loss and Body Mass Index than those less than 55 years old

Being overweight and unfit does not mean you cannot exercise

• Many obese and/or unfit patients believe that their obesity precludes physical activity
• Utilising our form of exercise those that are obese or morbidly so are able to improve their fitness levels and cardiorespiratory function to the same extent as their less weighty colleagues
• Additionally patients who are unfit (as established by high MHVO2/VO2 ratios) do equally as well as those who are fitter

The Benefits of Improved Fitness
Increasing fitness lowers the risk of death by 23%

• Fitter people have a 66% reduction in all cause mortality over unfit patients
• Additionally, there is a lower risk of developing cardiovascular risk factors when you are fitter
• Fitter people are also 3-6 times less likely to develop diabetes, high blood pressure and metabolic syndrome than those who are unfit

Increased fitness in men

• After completing six-weeks of interval training 76% of all men had above average fitness levels
• This was due to a 22% increase in physical fitness
• Their mean MHVO2/VO2 fitness ratio improved from 15.7 (average) to 12.3 (good) with a highly significant p-value of <0.0001

Better results for women

• Before completing the programme half of the women had below average fitness levels
• After six weeks only 16% still remained in this category
• The Rejuvenation Programme resulted in a 34% improvement in fitness, ensuring two-thirds of all women had above average fitness levels on completion
• Their mean MHVO2/VO2 fitness ratio to begin was 21.7 (poor) however this significantly improved (p<0.0001) to 14.4 (good) on completion

Being overweight and unfit does not mean you cannot exercise

• Many obese and/or unfit patients believe that their obesity precludes physical activity
• Utilising our form of exercise those that are obese or morbidly so are able to improve their fitness levels and cardiorespiratory function to the same extent as their less weighty colleagues
• Additionally patients who are unfit (as established by high MHVO2/VO2 ratios) do equally as well as those who are fitter

WHAT DO YOU NEED FROM US TO GET STARTED?

Improved cardiorespiratory function

• 6 weeks of interval training dramatically improves the heart’s ability to perform cardiac work by approximately 10-15% at all levels from rest to very heavy work, reducing the stress on the heart at any given workload (via reducing a measure known as the Pressure Rate Product)

As we exercise, both our heart rate and ejection pressure (blood pressure) must increase in proportion to the amount of work being done in order to fulfill the increased demand for blood by our muscles. The work being done by the heart is therefore equivalent to the heart rate ? ejection pressure I.e a measure called the Pressure Rate Product.

• Significant changes in total cholesterol
• Significant changes in HDL cholesterol
• Significant changes in triglycerides

• Significant changes in T/HDL ratio
• Significant changes in C/HDL ratio
• Significant changes in non-HDL cholesterol

Reducing Total Cholesterol

• Interval training was able to produce a highly significant decrease (p=0.0006) in mean total cholesterol levels across all patients in just six weeks with very little dietary change
• Additionally, those who had cholesterol levels in the highest quartile, or which were inadequately controlled by lipid-lowering medication, experienced greater reductions with changes in total cholesterol of 11% and 10% respectively (p<0.0001)

Non-HDL Cholesterol

• Non-HDL cholesterol includes all cholesterol present that is considered atherogenic (dangerous), including LDL, lipoprotein(a), intermediate-density lipoprotein, and very-low-density lipoprotein
• It is of increasing importance in risk analysis with suggestion that the non-HDL-C fraction may be a better tool for risk assessment than LDL cholesterol
• The Nu-life Programme was able to produce a highly significant (p<0.0001) reduction in this fraction from 4.02mmol/L to 3.80mmol/L in just six weeks

• Whilst significant changes (p<0.0001) in terms of weight loss and Body Mass Index occurred with the exercise programme after six weeks these changes will be accelerated if diet is modified and in particular, caloric intake is reduced.
• Those who are overweight or obese will benefit most

Being overweight and unfit does not mean you cannot exercise

• Many obese and/or unfit patients believe that their obesity precludes physical activity
• Utilising our form of exercise those that are obese or morbidly so are able to improve their fitness levels and cardiorespiratory function to the same extent as their less weighty colleagues
• Additionally patients who are unfit (as established by high MHVO2/VO2 ratios) do equally as well as those who are fitter

Compliance

• 20-30% of people give up cardiac exercise programs within 2-3 months
• This figure drops further, with less than half still exercising after a year

The Nu-life programme is individualised and designed with long-term lifestyle changes in mind. As a result 70-80% of patients are still exercising after one year and more importantly 60-70% have continued with the programme for two years or more.

Physical improvements in those with a prior heart attack

• Improvement in fitness ratio of 23% (p<0.0001)
• Highly significant improvements in Body Mass Index and weight
• Highly significant improvement (11%) in cardiorespiratory function at 2 and 4 METS of activity
• Significant lowering of systolic blood pressure by 10mmHg

Risk reduction in those with a prior heart attack and low HDL

• The Framingham Risk analysis is a measure of cardiac risk which takes into account several factors including age, sex, cholesterol, blood pressure, weight and smoking habits
• In patients who have suffered a heart attack and have low levels of HDL cholesterol a significant 41% reduction in 5 year risk occurs with the program