NNT and CV Drugs

Frank F. Vincenzi

October 22, 2006

Disclaimer

• Internal concerns and doubts about the relationship between the ‘health care system’ and industry and/or society

• Hans Rosling, Karolinska Institute• http://www.ted.com/index.php/talks/view/id/92?gclid=CIm6sq68io8CFRI5agodLBE8vQ

• Stephen Bezruchka, Senior Lecturer - Health Services, School of Public Health, University of Washington

• R. Nortin Hadler, Professor of Medicine and Microbiology Immunology, University of North Carolina, author of ‘The Last Well Patient, How to Stay Well Despite the Health Care System’

A few of my concerns - global• Increasing complexity of health care

• Loss of personal interaction between health care providers and patients

• Intrusive presence of ‘bean counters’ and emphasis on throughput of patients

• Decreased emphasis on wellness and increased emphasis on disease

• Expectations of perfection and reluctance to admit errors

• Student, resident and physician ‘burnout’

A few of my concerns - pharmacological

• Increased potency, selectivity (and adverse reactions) in newer drugs

• Increased drug usage and drug interactions

• Heavy reliance on surrogate end points as measures of risk of disease

• Increasing interdependence between the pharmaceutical industry and the:– FDA– Organized medicine

Stephen Bezruchka

• The US is the unhealthiest country among the developed nations, and yet spends over twice as much on ‘health care’ as more healthy countries.

• The health of populations around the world is inversely proportional to the differential between the richest and poorest members of the society.

• The political climate of a country (how the pie is divided) is more important to the health of the population than are the interventions of medicine.

Stephen Bezruchka (cont.)

• Japan, with the highest percentage of smokers in the world, has the longest life expectancy.

• ‘Eat right, exercise, lower your blood pressure, lower cholesterol, and wear a condom’…has relatively little effect on the overall health of a population.

R. Nortin Hadler

• ‘Medicalization’ is often well meant, but counterproductive.

• Telling a patient they have an elevated cholesterol medicalizes them, but may not actually change their life very much.

• With the exception of well-baby check ups and Pap smears, the annual physical examination provides no useful yield in an apparently well person.

R. Nortin Hadler (cont.)

• Two different views of wellness

– When are you going to die and what was the course of your life? (Life course epidemiology)

– What’s the proximate cause of death? (We can change what you die of, but can not change very much how long you live)

R. Nortin Hadler (on NPR)

• “We can predict about 70-80% of your mortal hazard with the answer to two questions”…

The West of ScotlandCoronary Prevention Study (WOSCOPS)

• News Release, Wednesday 15th November 1995

• LANDMARK STUDY :PRAVASTATIN RAPIDLY REDUCES RISK OF HEART ATTACKS AND SAVES LIVES OF PEOPLE WITH HIGH CHOLESTEROL AND NO PREVIOUS HEART ATTACK

The West of ScotlandCoronary Prevention Study (WOSCOPS)

• The WOSCOP study was a randomised, double-blind, placebo-controlled trial that included 6595 men between the ages of 45 and 64 who had elevated LDL-cholesterol levels (range = 155-232 mg/dL, or 4.0-6.0 mmol/L.) None of the participants had a previous heart attack. Mean follow-up was five years.

WOSCOPS Results

• Treatment with pravastatin reduced the risk of first-time heart attack and death, and the time-to-event curves began to diverge at six months after initiating therapy.

From an author of WOSCOPS…

• "We can say now with confidence that pravastatin reduces the risk of heart attack and death in a broad range of people - not just those with established heart disease, as has been previously proven, but also among those who are at risk for their first heart attack."

WOSCOPS Statistics

A little disclosure…

• The WOSCOP study was conducted by the University of Glasgow, Scotland and funded by a grant from Bristol-Myers Squibb.

Evidence-based medicine (more or less in increasing usefulness)

• Case reports– anecdotal

• Prevalence studies– cross sectional surveys

• Retrospective studies– case-control or case comparison

• Prospective studies– follow-up or longitudinal

• Randomized controlled trials (RCTs)– The gold standard

• Meta-analyses– The platinum-plated gold standard

Randomized Control Trial (RCT)

• Subjects are randomly* allocated into an experimental group or a control group and then followed over time for the variables or outcomes of interest– (blood pressure, HDL, LDL, first MI, second stroke,

death, etc.)

*Experimental treatment is assigned if a virtual coin toss lands “heads” and a conventional, “control” or “placebo” treatment is given if virtual coin lands “tails”

Event Rates

• Experimental event rate (EER)– Proportion of patient in experimental group

demonstrating the defined event

• Control event rate (CER)– Proportion of patient in control group

demonstrating the defined event

Calculating Risk Reduction

• Relative risk reduction (RRR) =[EER-CER]/CER

Absolute risk reduction (ARR) =[EER-CER]*

* [xx] used here to designate the absolute value of xx. (Proper vertical lines look like the letter I).

Number Needed to Treat (NNT)

• The number of patients that need to be treated to prevent one bad outcome

• Calculated as the inverse of the absolute risk reduction

Trimethoprim-sulfamethoxazole for prevention of infection in hepatic cirrhosis

CER = 9/30 = 0.300

EER = 1/30 = 0.033

RRR = [0.033-0.300]/0.300 = .89

ARR = [0.033-0.300] = 0.267

NNT = 1/0.267 = 3.74

Simvastatin: More Clinical Trials

Scandinavian Simvastatin Survival Study (4S) Group (1994; 1995; 1996; 1998)

The Long term Intervention with Pravastatin in Ischemic Disease (LIPID) (1998)

(Reduction of fatal and non-fatal CHD events, strokes and total mortality. Rates of adverse events in placebo and drug groups were not significantly different)

Decreased mortality in

patients treated with simvastatin

NNT estimated from Kaplan-Meier Curves

• Alive 0.925 vs. 0.905, mortality rates =0.075 and 0.095, respectively

EER = 0.075CER = 0.095Event Rate Ratio = 0.075/0.095 = 0.79

And:

ARR = [0.075-0.095] = 0.020

NNT = 1/0.020 = 50

So…RRR ~ 21%

Simvastatin: A more recent large trial

Heart Protection Study Group*MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trialLancet 360: 7-22, 2002

40-80 y/o, coronary disease, other occlusive arterial disease or diabetes

40 mg simvastatin daily (85% compliance/matching placebo (17% non-study statin use), intention to treat comparison (85%-17%)

5 years, average difference in LDL of 1.0 mmol/L

Heart Protection Study (HPS)Significant* decreases in:

all cause mortalitycoronary death rateother vascular deaths

non-fatal MInon-fatal or fatal stroke

Non-significant decrease in:non-vascular deaths

* (After 1 year of 5)

Lancet 360: 7-22, 2002

HPS: Effect of simvastatin on first major vascular event in different prior disease categories

Heart Protection Study

“…among the many types of high-risk individual studies, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends on such individuals’ overall risk of major vascular events, rather than on their blood lipid concentrations alone.”

Lancet 360: 7-22, 2002

Some selected adverse reactions to statinsGreater than 1% and greater than placebo

constipationdiarrheadyspepsiaflatulence

Reported:muscle cramps, myalgia, tremor, dizziness, vertigo, memory loss, paresthesia, peripheral neuropathy, psychic disturbances, anxiety, insomnia depression, pancreatitis, hepatitis, cholestatic jaundice, gynecomastia, loss of libido, erectile dysfunction

AND: Myopathy/rhabdomyolysis

Monograph for simvastatin, Zocor® PDR, 2006

Controlled Clinical Trials vs. actual practice

Adverse reactions to statins may be substantially increased when they are combined with other agents:

Increased risk of myopathy and rhabdomyolysis (and irreversible kidney damage) when statins are combined with:

niacin or fibric acids (pharmacodynamically additive inhibition of muscle sterol synthesis)

agents that may inhibit CYP enzymes such as erythromycin or itraconazole, etc.

(most statins are metabolized* by CYP 3A4).

*pravastatin is excreted unchanged

Simvastatin cost ($) for 5 years?

• Drugstore.com 10/18/06

– Simvastatin (generic) = $7080/5 years– Zocor® = $8120/5 years

Tonkin et al., Am Heart J 2006; 151, 1305-1312

• Cost-effectiveness of cholesterol-lowering therapy with pravastatin in patients with previous acute coronary sydromes aged 65-74 years compared with younger patients: Results from the LIPID study

• Estimated additional life-years saved from pravastatin therapy were 0.39 years for older and 0.40 years for younger patients. Incremental costs per life-year saved were A$7581 in the older and A$14994 in the younger, if discounted at 5% per annum (calculated in 1998 Australian dollars)

• ‘did not evaluate the effect of treatment on the quality of life’

Tonkin et al., Am Heart J 2006; 151, 1305-1312(comments by ePocrates docalerts)

• An additional ~4.8 months per average patient

• For every 1000 patients aged 65-74, pravastatin treatment for 6 years prevents 43 deaths at a cost of A$2.1 million, or A$55474 per life saved.

• Younger patients - A$167,161 per life saved.

• The researchers did not evaluate the effect of treatment on the quality of life

• “These estimates were not adjusted for the quality of life; thus the quality of life saved in the younger group could be better than that of a life saved in the older group.”

Evidence-based Medicine(maybe a pinch, or at least a grain, of salt)

• Smith, GCS and Pell, JP, Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials, BMJ 327:1459-1461, 2003

What is already known

• Parachutes are used widely used to prevent death and major injury associated with gravitational challenge

• Parachute use is associated with adverse effects due to failure of the intervention and iatrogenic injury

• Studies of free fall do not show 100% mortality

Smith and Pell (2003)

What this study adds

• No randomised controlled trials of parachute use have been undertaken

• The basis for parachute use is purely observational and its apparent efficacy could potentially be explained by a ‘healthy cohort’ effect

• Individuals who insist that all interventions need to be validated by a randomised controlled trial need to come down to earth with a bump

Smith and Pell (2003)