BATTLING A BEAST WITH MANY HEADS
Whether it's about risk factors or drug trials, CVD studies over the years have so far led up to the clinical wisdom that the disease can only be grappled with in multiples.
By Grace Roxas, Contributing writer
Ancient Greek legend talks about the Hydra, a monstrous being whose final defeat came only when each of its many regenerating heads were cut and cauterized in one master stroke.
It was only in 1948, in the small town of Framingham, Massachusetts, that the medical world began grappling with a shadowy form of a modern-day Hydra: a disease that rears many an ugly head with the multiple risk factors it invokes.
Cardiovascular disease ( CVD ) has also sparked many quests for solutions, some more groundbreaking than others and are, in homage to another Greek legend, Protean, in their clinical utility. These landmark findings lend themselves good platforms for the ultimate challenge that faces each clinician: distilling the cumulative knowledge from CVD research through the years to fit each patient's unique tangle of risks.
View from Framingham
The size of the Framingham Heart Study's original cohort, 5,209 overtly healthy men and women aged 30 to 62, or those of succeeding generations hardly seems to qualify as epic, compared with many latter-day, large-population studies.
But this prospective longitudinal study, which is still running today, not only gave the world a rich medical-research database for studying the common characteristics, including genetic ones, that contribute to CVD over a long period of time.
It was also the first to propose now-familiar concepts about the disease, including the very idea of "risk factors." Framingham first raised the alarm regarding cigarette smoking, abnormal cholesterol and blood-pressure levels, electrocardiogram abnormalities, obesity, psychosocial factors, and menopause in connection with heart disease. High blood pressure was found to increase the risk of stroke and the progression from hypertension to heart failure was first described.
Physical activity and high levels of high-density lipoproteins (HDL), on the other hand, were found to reduce the risk of heart disease and mortality respectively.
"What's good with Framingham is that it was the first to establish that it's the person who's responsible for his heart disease," said cardiologist Gilbert Vilela. "There are risk factors that you should avoid or treat or manipulate or intervene with so that it wouldn't lead to heart attack. In the 1940s, people's idea about atherosclerosis and heart disease was close to zero. Para bang it was a curse or a race thing."
In latter years, the rich database from the study has also been employed for collaborative work on stroke and dementia, osteoporosis and arthritis, nutrition, diabetes, eye diseases, and genetic patterns of common diseases.
The narrow demographics of the study, especially with the rise of cardiovascular disease as a global menace, is a common criticism leveled against it, although, said Vilela, comparative studies with other populations have validated the Framingham findings.
He added: "When it comes to risk, I think it's the same around the world. The main difference is only in the population-attributable risk (PAR) or what is prevalent in a particular place. That's the bigger danger."
This perceived limitation of what is otherwise deemed a truly landmark research initiative only encouraged others to duplicate it in their local settings. In the Philippines, there are at least two known efforts in this direction: an industry-based study among employees of Philippine conglomerate San Miguel Corporation that started in the late 1960s up to the early 2000s, and a community-based one initiated in 2002 by St. Luke's Medical Center in a barrio in Batangas.
Noted cardiologist Ramon Abarquez, who was personally involved with the San Miguel study, cited as a good model the long-term, regular surveillance done in Framingham, as it enabled better assessment of the significance of each risk factor as it occurs in different patients. Framingham participants undergo extensive physical examinations and lifestyle interviews every two years.
"A patient with a longer period of untreated hypertension can be more at risk than a patient with a recent-onset hypertension," Abarquez explained. "As with Framingham, we were able to detect the onset of high blood pressure in the San Miguel study because of the annual employee checkup, unlike in other hypertension studies where there's no sure way of knowing how long a newly recruited subject has been hypertensive."
Going global
In 1999, the INTERHEART study finally filled a growing gap in CVD research by documenting incidence of potentially modifiable risk factors on a global scale. Study investigators note that although 80 percent of the global disease burden is borne by low- and middle-income countries like the Philippines, data on risk factors largely come from developed countries. As a result, little is known about the effects of such risks in most regions of the world.
The Philippines was one of the 52 countries included in INTERHEART, a standardized, case-control study of association between risk factors and the occurrence of first acute myocardial infarction (MI). It involved more than 30,000 subjects representing all inhabited continents.
They were divided into two groups: those with incidences of new MIs and a sex-matched and age-matched control population. Cases and controls were enrolled until 2003. For a small percentage of the controls, repeat measures of risk factors were done at a median interval of 409 days.
Aside from looking at the risk-factor correlation in the overall study population, variations of this relationship were examined by geographic region, ethnic origin, sex, or age. PAR estimates for risk factors took into account combinations found in the overall population and in various subgroups.
"The global scope of INTERHEART and the fact that it included the Philippines makes it very relevant. It becomes an actual-practice scenario in our country rather than an extrapolation of foreign data into our setting," Abarquez said.
The results validated earlier findings, particularly Framingham's, and then some. Fruits and vegetable consumption and alcohol intake were factored in for the first time and the risks were ranked in importance.
Abnormal lipids emerged as the top risk factor associated with a first heart attack, followed in order by smoking, psychosocial factors, diabetes, history of hypertension, abdominal obesity, alcohol consumption, physical activity, and fruits and vegetable intake. These nine risk factors were found to account for 90 percent (men) and 94 percent (women) of the PAR.
Abarquez said that while there may be slight differences between the sequences of INTERHEAT's risk-factor rankings and those based from in-country surveys, the commonality of risk factors is in itself significant. He noted that hypertension is found to be the leading risk factor in the Philippines while in the US, obesity is becoming the major issue.
The INTERHEART results likewise suggested that approaches to prevention can be based on similar principles worldwide and can have the potential to prevent most premature cases of MI.
Vilela noted that the inclusion of fruits and vegetable intake as a risk factor serves notice that it is no longer enough to just shy away from fatty foods to avoid coronary heart disease, as was the conventional wisdom.
The emergence of psychosocial factors as a crucial risk factor also holds special relevance, especially in the Philippines. "Major life events, like the various natural and manmade calamities that we have been experiencing, are psychosocial stresses. Acute mental stress can cause heart attack or kung may sakit ka na sa puso, pwede nyang iaggravate [ang] sakit mo," Vilela observed.
That there is more to addressing these risk factors than pure medication is indicated by the residual risk that Vilela said is always present in any graph of clinical studies. "A doctor should always include advice regarding stress management and patient education in treatment. What these studies are telling us is that we should use them in our practice as doctors and governments should use them as basis for starting programs on lifestyle change."
Abarquez said that he sees INTERHEART and similar studies as a jump-off point to a broader understanding of the role played by risk factors. "It is the clustering of risk factors that is more important, not the individual risk. That is the current message now. So if you're hypertensive, there's a likelihood that you are also a smoker. And in some instances, you may have diabetes or you might be overweight."
Protecting the heart
On the treatment side, a 1994 large-scale trial on the use of statin for prolonged cholesterol lowering led to some major rethinking among medical practitioners.
For Vilela, the Heart Protection Study (HPS) initiated a paradigm shift in the way he manages risk in his patients. "Before HPS, we were treating patients based on the so-called target levels. We went by certain action thresholds in cholesterol levels that should be breached first before we would recommend statin therapy," he said.
HPS is a randomized, double-blind trial among 20,536 individuals aged 40 to 80 years, who were at high risk from coronary heart disease but for whom there was substantial uncertainty about the balance of benefits from a cholesterol-lowering therapy.
With a daily dose of 40-mg simvastatin versus placebo at an average follow-up of five years, risk of major vascular events (notably MIs and strokes) went down by at least a third among the treated patients.
Reduced risk from further major vascular events and deaths were noted even among people who already had previous MI or stroke. The treatment benefits increased throughout the treatment period, leading to the conclusion that extended use of a statin can bring even greater benefits.
These benefits were said to add to those gained from other medications for MI and stroke prevention, like aspirin and hypertension drugs. There was also no evidence found linking cholesterol lowering with nonvascular causes of deaths such as cancers and strokes induced by bleeding.
The uncertainty it resolved among patients who were questionable candidates for statin therapy dovetails with the emphasis on risk factors in studies like Framingham and INTERHEART. Vilela said HPS taught him not to treat by the numbers but in terms of the level of risk.
"HPS says that regardless of the level of low-density lipids (LDL), if a patient is high-risk, you should already treat," he said. "In real practice, most of the people we see in the clinic are already high-risk. Konting konti lang ang low-risk."
The dynamics of risk factor clustering in each individual patient, however, is precisely what makes Abarquez quite skeptical of most studies that are used for setting treatment guidelines. "We do know that the hard end points are dependent on the individual with the most risk. In other words, most studies do not tell us whether the subject who is hypertensive also has diabetes and obesity, is a smoker, and has high cholesterol."
Hats off to ALLHAT?
In 1994, the Anti-Hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the largest study of its kind to date, sought to establish a definitive first-line treatment for hypertension. It directly pitted diuretics (chlortalidone) with newer hypertensive agents, namely, calcium-channel blockers (amlopidine), angiotensin-converting-enzyme inhibitors (lisinopril), and alpha-blockers (doxazosin) in a trial involving 42,418 patients.
As a corollary, the lipid-lowering properties of the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin were examined in connection with mortality reduction among older hypertensives.
At the end of its eight-year course, this randomized, double-blind, multicenter trial came away with the conclusion that thiazide-type diuretics remain the drug of choice for first-step, antihypertensive therapy because of their apparent superiority in preventing one or more major forms of cardiovascular disease and their lower cost. CCBs and ACEIs may be considered, however, for patients who cannot take diuretics.
While the results of the hypertensive phase reassured practitioners that an older-generation treatment like diuretics could still deliver benefits, some critical treatment considerations in hypertension and beyond may have been missed.
Pointed out Abarquez: "All antihypertensives have the same blood-pressure-lowering effects but the difference is in the level of exposure to risk of new-onset diabetes, which is now a major attribute in choosing an antihypertensive agent. Diuretics happen to be one such agent that will give this greater risk and this is my personal objection to preferring it over the others."
For obese hypertensives, the doctor should carefully weigh their simultaneous risks for salt retention and high triglycerides with low HDL, a marker of insulin resistance and precursor for new-onset diabetes that is often found in the obese. It boils down again to a highly personalized approach and knowing one's patient, he added.
Vilela said that ALLHAT somehow misses the forest for the trees. "Blood pressure is just, kung baga sa lagnat, thermometer lang yan. Its just an indicator of how well your medicine is doing, but its not going to save or cure your patient because the disease is vascular. When we give medication, it should not just be to bring down blood pressure but to stop the progressive, unrelenting inflammatory disease called atherosclerosis."
While the study recognized that most hypertensives require more than just one drug, Vilela observed that it tends toward monotherapy. He himself adheres to the double-therapy approach at the outset for faster control of blood pressure and to go beyond addressing just the hypertension.
As for the lower cost of diuretics, he conceded that it might be a relevant concern in the Philippines but that there are now generic versions of the newer hypertensive agents. He said: "As a doctor, ethics dictate that hindi mo pwedeng ipagpalit kung ano ang tama with what's merely cheap."
The European view
The safety and efficacy of CCBs for elderly patients were the focus of the Systolic Hypertension in Europe Trial (Syst-Eur), a randomized, double-blind, placebo-controlled trial started in 1989, with an extended five-year study, which ended in 2003.
Afflicting an estimated 15 percent of people aged 60 years and above worldwide, systolic hypertension is expected to affect a bigger percentage as the "baby boomer" generation or those born during the population boom after World War II reaches old age.
Using nitrendipine, Syst-Eur's primary end point was fatal and nonfatal stroke combined. So significant were the early returns from the study that the nearly 5,000 patients over 60 years old who participated were followed up for only an average of two years.
The primary end point was reduced by 42 percent, and other fatal and nonfatal cardiac end points (e.g. sudden death) went down by 26 percent. Heart-attack deaths alone went down by 56 percent. No increase was found in noncardiovascular deaths, including cancer, or any forms of bleeding.
In clinical terms, treating 1,000 elderly patients with isolated systolic hypertension for five years would prevent 29 strokes or 53 major cardiovascular events.
Vilela agreed that for elderly hypertensives, CCBs are the best first-line treatment, owing to the elderly's higher risk for strokes. "I noticed that CCBs bring down the blood pressure faster compared to diuretics plus beta-blockers. And a fast-acting drug is especially important for the cluster of risks associated with an older hypertensive patient."
HOPE and EUROPA
Heart Outcomes Prevention Evaluation (HOPE) and EUropean Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) are two similarly designed (randomized, double-blind, placebo-controlled) clinical trials that established the utility of ACEIs at the intermediate, pre-heart-failure stages of the cardiovascular disease continuum. ACEIs have also been previously tested for efficacy at the extreme end of the continuum: for severe heart failure.
HOPE was geared to determine whether the use of the ACEI ramipril could reduce the rate of mortality, myocardial infarction, and stroke in high-risk patients. These are individuals with evidence of vascular disease or diabetes plus one other CVD risk factor but who are not known to have a low ejection fraction or heart failure.
Nearly 10,000 patients aged 55 years and above were followed up for an average of 4.5 years to track the primary end points of MI, stroke, and cardiovascular death as a composite and as separate outcomes. Aside from ramipril, vitamin C was administered to half of the population in the treatment and control groups.
A significant 22-percent risk reduction was noted for the composite primary end points. For two secondary end points, revascularization and diabetes-mellitus complications, 16-percent and 32-percent lower risks were registered.
Investigators noted clear benefits across the board, among patients with or without evidence of coronary-artery disease (CAD) at baseline, with or without a history of MI, with a documented ejection fraction greater than 40 percent, and whether or not patients were taking in other cardiovascular medications.
The use of vitamin C produced nonsignificant results, affirming earlier outcomes from the use of antioxidants vitamins E, C, and beta-carotene in the HPS study.
EUROPA investigated the prevention of cardiovascular morbidity and mortality with the ACEI perindopril in patients with proven stable CAD, defined as either a previous MI or surgery or revascularization, but without heart failure. Unlike HOPE, the more than 12,000 participants in this trial included people in their mid-20s with follow-up averaging four years. Investigators noted that CAD is one of the biggest causes of death worldwide but the long-term efficacy of ACEIs in CAD patients has never been investigated or established.
The final analysis showed a reduction of cardiovascular deaths, MI, and cardiac arrest (primary end points) by 20 percent, fatal and nonfatal MI by 24 percent, and heart failure by 39 percent.
Said Vilela: "These two studies prove that we now have a medication na sa umpisa pa lang, maasahan mo na. You can be aggressive if you want to.... Using ACEIs is similar to making a surgical cut. It immediately helps because of its impact in slowing down the unrelenting process of atherosclerosis."
Huge investment
INVEST (INternational VErapamil SR/trandolapril STudy) compared the effects of two different treatment regiments, CCBs and beta-blockers, for patients with coexisting hypertension and CAD, a large population that is particularly vulnerable to MI or stroke.
With more than 22,500 participants from 14 countries followed up for an average of 2.7 years, the 1997-2003 trial was a randomized, prospective, controlled study that did a head-to-head comparison of verapamil, a nondihydropyridine CCB, and the beta-blocker atenolol.
The verapamil arm allowed the addition of the ACEI trandolapril and the addition of the diuretic hydrochlorothiazide (HCTZ) if needed. The atenolol arm allowed for HCTZ and trandolapril as needed.
Based on the primary end points of first occurrence of all-cause death, nonfatal MI, or nonfatal stroke and secondary outcomes in terms of blood pressure control, angina pectoris, and new onset diabetes, the two regimens showed equivalent clinical outcomes. For either strategy, investigators noted that most patients would require multiple drugs to achieve blood-pressure goals.
For the prevention of death and diabetes through a verapamil SR-based treatment, they recommended further study to map out possible public-health implications. Abarquez noted that although the key outcomes were the same, new-onset diabetes was fewer in the verapamil group, and there was better control of the anginal effect and progression to heart failure with the latter regimen.
With beta-blockers deemed as a kind of gold standard prior to the study, INVEST, he said, merely implies that there is now an alternative that is just as good as beta-blockers for CAD and hypertension. "I wouldn't like to use a beta-blocker among smokers because of the risk of asthma, peripheral-artery disease, and its adverse effects on lipids," he added.
But he said that beta-blockers retain their turf in acute MI treatment. "In a study on angioplasty, having a beta-blocker on board is found to have a better effect. Without beta-blockers, there was no difference with medical treatment of thrombolysis."
Charming results
CHARM (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) is a threefold clinical trial investigating the efficacy of the ARB candesartan in reducing mortality and morbidity among patients with chronic heart failure.
The three arms of the trial deployed candesartan as an alternative for patients intolerant to ACEIs (CHARM-Alternative), as an add-on to ACEIs for patients with low ejection fraction (CHARM-Added), and as an add-on for patients with preserved ejection fraction (CHARM-Preserved).
For the overall program, all-cause mortality was the primary end point and for the three components, cardiovascular death and hospital admission for chronic heart failure were considered key outcomes.
More than 7,500 patients as young as 18 years old with symptomatic heart failure of at least four weeks' duration, participated in the parallel, randomized, double-blind, placebo-controlled trials, which also allowed the use of conventional heart-failure treatment.
After an average patient follow-up of more than three years, 23 percent of patients in the candesartan group and 25 percent of those in the placebo group died, with fewer cardiovascular deaths (18 percent v. 20 percent) and hospital admission for chronic heart failure (20 percent v. 24 percent in the candesartan group.
Investigators noted "no significant heterogeneity" for candesartan results across all three component trials. Furthermore, candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for heart failure. Ejection fraction and treatment at baseline did not seem to alter these effects.
For Abarquez, it is harder to attribute isolated results for individual medications in a heart-failure study, since most heart-failure trials involve combination therapies. The CHARM trials are no exception, he said, with only about 15 percent representing ARB monotherapy and the rest has at least a diuretic included.
"Unless you have set a serum drug level, it is very hard to credit benefits to a particular drug when you are using it in combination," he explained.
Although Vilela cited the results of the CHARM-Alternative and CHARM-Added as significant, he believes that the main implication of the study is presenting ARB as an alternative for heart-failure patients who get coughing fits with ACEIs.
"But for those who don't have heart failure and stroke, that remains the turf of ACEIs," he added.
Going proactive
As a clinical trial investigating the use of the oral hypoglycemic drug pioglitazone in preventing the progression of macrovascular disease, PROACTIVE (Prospective Pioglitazone Clinical Trial in Macrovascular Events) underscores the pleiotropic potential of a new class of drugs in the cardiometabolic nexus.
Macrovascular disease is associated with cardiovascular morbidity and mortality in type 2 diabetes. More than 5,000 type 2 diabetes patients in 19 European countries, aged 35 to 75, underwent trial with the drug over a minimum of 2.5 years, keeping in mind a mix of cardiovascular and metabolic primary end points. Piaglitazone was combined with existing therapy in this placebo-controlled trial.
Primary outcomes were all-cause mortality, nonfatal (including silent) MI, stroke, major leg amputation, acute coronary syndrome, cardiac intervention including coronary-artery bypass graft or percutaneous coronary intervention, and leg revascularization.
On the cardiovascular side, there was a 10-percent relative risk reduction in the primary end point and 16-percent relative risk reduction in the principal secondary end point of all-cause mortality, stroke, and nonfatal MI. On the metabolic side, there was a decrease in glycosylated hemoglobin, reduction in progression to permanent insulin use, improved diabetic dyslipidemia, and blood-pressure reduction.
In clinical terms, adding pioglitazone to the medication of 1,000 patients would avoid 21 first MIs, strokes, or deaths over three years. Forty-eight patients would need to be treated for three years to avoid one first major CVD event.
Vilela sees a big potential in the mechanism of action of piaglitazone and similar class of drugs like rosiglitazone. However, the duration of the study itself is too short, in his estimation, to establish the drug's claims.
He said: "Remember that piaglitazone is claiming to be antiinflammatory and antiatherosclerotic, but you cannot stop atherosclerosis in just three years. Dapat at least five to seven years. The standard deviation only indicates a trend so there's still a high probability that the 10-percent risk reduction is a chance happening."
Nevertheless, he said he prescribes this class of drugs and he has a good experience with them. He said: "Maganda ang experience ko with the drugs because I choose my patients well. I will not give those drugs to heart failure patients for example since they increase the absorption of water, which may increase risk of heart failure."
Abarquez said that it is clinically useful to presume that diabetics have the heart of a nondiabetic who already had an MI. "We should treat the heart of a diabetic even if there is no heart failure. This means there is already a diastolic dysfunction, which has the same mortality risk as systolic dysfunction," he explained.
A galaxy of trials
STELLAR (Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses) is one of the major completed trials under the GALAXY program, a series of clinical studies focused on rosuvastatin. The program seeks to confirm whether the statin with the best effects on the atherogenic lipid profile and beneficial changes on inflammatory markers will deliver profound benefits on atherosclerosis, in turn leading to the best reductions in cardiovascular morbidity and mortality.
The main thrust of this six-week, parallel-group, open-label, randomized trial was to make comparisons with the other statin preparations across dose ranges (10, 20, 40, or 80 mg) to reduce LDL among 2,431 adults with hypercholesterolemia.
End-trial analyses showed that rosuvastatin caused mean change in HDL of between 7.7 percent to 9.6 percent, compared with 2.1 percent to 6.8 percent with the other statins. LDL-reduction rates were consistently higher from rosuvastatin, compared with each of the other statins: 8.2-percent more than atorvastatin (10 and 80 mg), 26-percent more than pravastatin (10 and 40 mg), and 12-percent and 18-percent more than simvastatin (10 and 80 mg). M
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