Dr. Qaadri

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Heart Disease and Heart Protection

By Dr. Shafiq Qaadri, MD

How are we doing in terms of our management of cardiovascular risk?
Generally, the medical community and allied health professionals have done a great job over the past few decades; as witnessed by the fairly dramatic reduction in cardiovascular mortality rates, not only in Canada, but in most of the western world. Having said that, there are two areas of concern; one, that despite the successes, cardiovascular disease still remains the number one cause of premature death in Canada. So, there’s a lot more work to do. The second concern is that in recent years, the gains that have been made in reducing cardiovascular mortality seem to be plateauing. Now, it’s hard to know that until we wait another few years and look at the data retrospectively, but certainly the slope of the survival curve over time does seem to be slowing down. One possible explanation for that is the epidemic that we have now of abdominal obesity, dysglycemia, type II diabetes; and if this is true, then some of the gains of the past several decades may actually be erased.

Outcomes have been falling, but yet we have plateaued. I think it is important for family physicians to recognize that the most common risk factors are not optimally treated to goal…Consider hypertension. Today in primary care, I would say over 50 per cent of people who see primary care physicians, are not adequately managed with respect to getting to target. Furthermore, understanding the choices we make in pharmacotherapy has an impact on these outcome rates.

It is also important to recognize that the transition the transition from coronary artery disease to developing a myocardial infarction is just one second. So, really, it is an artificial distinction in our mind that we say patients who have “stable coronary artery disease,” who then transition the next morning into an acute coronary syndrome

What is the cardiovascular continuum and what implications does that have for family practitioners?
The cardiovascular continuum was proposed about 15 years ago by Dr. Victor Dzau. It represents a sequence wherein risk factors lead to eventual development of atherosclerosis; atherosclerosis then sets the stage for the development of left ventricular dysfunction, myocardial infarction and heart failure…It has really set the stage for the interrogation of the continuum with respect to intervention strategies; the RAAS System [Renin Angiotensin Aldosterone system] has been the most well studied system across the continuum of cardiovascular risks.

I would add that, although the continuum has been proposed as a simplistic sequential model, wherein risk factors eventually lead to atherosclerosis, there are many patients who may actually skip a number of steps and go directly from a risk factor to an event.

The other practical point for family physicians about the cardiovascular continuum is that 15 or 20 years into this construct, we now know that intervention at almost any stage of this continuum can prevent progression to the next level or to a clinical event. So, intervention on risk factors, whether it is the management of hypertension, diabetes or lipids, can prevent the development of atherosclerosis.

Intervention, once atherosclerosis is present, can reduce the likelihood of an event and once the patient has had an event, intervention can reduce the likelihood of mortality or a recurrent event. I think that’s very important for primary care physicians to realize.

What is the RAAS system, and why is it gaining so much attention?
The Renin Angiotensin Aldosterone System. Initially, it was proposed to be a system that predominately existed within the kidney, playing a very vital role in the pathophysiology of diabetic nephropathy. It has now been implicated as a critical system in many organ systems, including the vasculature and the heart. We have learned that strategies that inhibit this gateway, whether it is using an ACE inhibitor or an ARB, which are sort of “RAAS Inhibitors” or a strategy, such as direct renin inhibitors, which are aimed at the point of activation, may be extremely useful pharmacological agents.

What are the challenges with regard to risk reduction therapy, especially in patients over 65?
In patients over 65, compliance seems to be the Achilles heel. If people do not stay on therapy, they certainly will not derive any benefit. Issues include side effects, cost, it multiple drug use, and so on.

What are the key findings and clinical implications in terms of heart failure management of the UMPIRE study.
The UMPIRE study was performed at the Institute of Clinical Evaluative Sciences at the University of Toronto. This is a premier organization which evaluates population-based outcomes in over 1.5 million Ontario residents over the age of 65. The unique attributes of the ICES database is that they have the ability to link prescription claims data with hospital admission and outcomes for a variety of different interventions.

The UMPIRE study was a straightforward question that we addressed in Ontario. We asked whether the strategy of RAAS blockade with an ACE inhibitor or an ARB, employed over the past few years by family physicians and specialists, had a different outcomes with respect to myocardial infarction or acute coronary syndrome hospital admission. This study demonstrated that in an over 72,000-person-year follow-up, clearly a large follow-up, is that there was no difference with respect to the primary outcome, i.e., myocardial infarction or acute coronary syndrome in users of ACE inhibitors or ARB.

So, said differently, in all comers in Ontario over the age of 65, the strategy of RAAS blockade did not change the outcome of hospital admissions for MI or ACS. What was very interesting was that these agents are widely used in people with different risks, i.e. diabetes, heart failure and atherosclerosis; and in these three sub-groups again, there was a clear trend towards superiority of being on an ARB versus being on an ACE inhibitor.

What was even more interesting was in the highest risk patient, i.e. someone who has had a previous myocardial infarction, a new strategy of choosing either an ACE or an ARB revealed that users of ARBs had a 32 per cent relative risk reduction, significantly in favour of using an ARB over using an ACE inhibitor.

To sum it up, the UMPIRE audit of our own backyard in Ontario demonstrates that what is probably much more important is choosing an RAAS inhibitor that people are compliant with, because really the outcome were not different with respect to myocardial infarction or acute coronary syndrome. Clearly, there was better compliance in UMPIRE consistent with other observations from Saskatchewan, demonstrating that probably the best therapy with respect to compliance in this out-patient population is an angiotensin receptor blocker.

Should family doctors think that ARBs and ACEs are relatively interchangeable, or is there a fairly distinct difference?
No, family doctors for awhile have struggled with this concept. They have used ACE inhibitors first, and if people are intolerant of an ACE inhibitor, they use an ARB.

This very large population-based study from Canada gives us a snapshot that the choice of RAAS blockade may not influence outcomes with respect to myocardial infarction and acute coronary syndrome, i.e. they are interchangeable—but there is better compliance with ARBs; furthermore, better compliance may be one of the reasons in post-MI patients, for example,that there was actually a superior benefit of ARBs over an ACE inhibitor.

It’s important to recognize that this is a population-based study and, obviously, does not trump any randomized-controlled trial.

What are the current key theories with regard to ethnocultural background as a newly appreciated risk factor for the cardiovascular continuum?
We’ve learned again over the past couple of decades that people of varying ethnic origin actually have varying risks for developing different cardiovascular diseases. Once risk factors or the disease itself is established, ethnicity also can differentiate in terms of outcomes.

This was most noticeably apparent in the African-American population with, for example, hypertension and the heightened risk of renal failure and stroke compared to other populations with the same degree of hypertension.

In Canada, our two largest visible minorities are Chinese-Canadians and South Asians; in fact, a Canadian study called SHARE a few years ago by my colleague Sonia Anand from McMaster, showed us that Canadians of three ethnic groups--South Asians, Chinese and white caucasians living in Canada, actually had very different risk factor profiles for cardiovascular disease, and different outcomes in terms of the degree of atherosclerosis, which could not be fully explained by traditional risk factors.

To make a long story short, it appears that South Asians particularly are at uniquely increased risk for the development of both type II diabetes and premature atherosclerosis. The majority of that increased risk is likely attributable to the common risk factors that we all know about, but it appears that South Asians accrue those risk factors at an earlier age; if you accrue risk factors at an earlier age, you develop disease at an earlier age.

Do our current strategies for estimating risk, for example, Framingham, mildly or severely underestimate risk?
It’s fairly well agreed upon that the Framingham Risk Score is a very reasonable intermediate term estimate of cardiovascular risk in populations in whom the Score has been validated, which is largely the white caucasian population in North America. Having said that, there are numerous publications that demonstrate that the Framingham Risk Score by itself likely underestimates cardiovascular risk in certain ethnic groups, particularly in South Asians; it is likely a reasonable risk estimate in black or African-American populations, and probably overestimates risk in the East Asian population, such as Chinese and Japanese groups.

There is talk that a simple waist measurement, done at the family practice level or at home, is apparently a very powerful predictor. Is it the new vital sign?
Waist circumference clearly should be adopted as an additional vital sign by primary care physicians across Canada. We have a wealth of data now that supports the fact that a single measurement of waist circumference, much as a single measurement of LDL cholesterol or systolic blood pressure, predicts long term outcome both in terms of risk for the development of diabetes and risk for the development of cardiovascular disease and mortality, independent of other risk factors. Waist circumference is a crude measure or estimate of the presence of excess abdominal or visceral fat.

There are two types of fat. One is subcutaneous fat, i.e. fat under the skin, and the other is fat that is around the organs, that is entitled visceral fat. Over the past few years, we have understood that adipocytes, particularly the fat around organs, is very metabolically active. In fact, this fat secretes a number of adipokines, which are hormones that are released from the adipose tissue, just like insulin is released from the pancreas and thyroid hormone is released from the thyroid gland.

These adipokines have the potential to speak different languages: on the one hand, they can facilitate the development of insulin resistance, and on the other hand, they can spill over into the circulation and actually have direct influences on the development of cardiovascular disease.

What are the emerging strategies to block the RAAS System?
The tried and true, well-understood message to block the Renin-Angiotensin Aldosterone System includes ACE inhibitors and Angiotensin Receptor Blockers, as well as Aldosterone antagonists.

The newest strategy involves actually blocking the system right at the entry point. Renin facilitates the conversion of angiotensinogen to angiotensin I, which is the substrate for the ACE enzymes. ACE inhibitors block the conversion of angiotensin I to angiotensin II. Therefore, the entire RAAS cascade is dependant on renin.

The newest strategy is a new class of drugs in development called direct renin inhibitors, or DRIs. The first agent known is aliskerin, which is not yet available in Canada…This drug basically binds to renin in a manner that prevents renin from facilitating the conversion of angiotensinogen to angiotensin I. What’s particularly attractive about this concept is not only that you are blocking the system right at the entry point, but in general, what many physicians don’t appreciate is that they think that the RAAS System is a linear cascade that ends effectively with angiotensin II binding to its receptors.

In fact, there is a negative feedback loop. So, when angiotensin II exerts its effect, that results in activation of plasma renin activity. When we inhibit the RAAS system, with either ACE inhibitors or ARBs, we actually get a rebound increase in plasma renin activity because we are in a sense inhibiting that negative feedback loop. So, ACE inhibitors and ARBs are associated with an increase in plasma renin activity.

Uniquely, direct renin inhibitors such as aliskerin not only block the RAAS system, but also reduce plasma renin activity and plasma renin activity independently has been tied to adverse risk.

Is it conceivable that a hard to treat hypertensive, multisystemic patient could be on all three agents? What is the experience with DRIs in terms of efficacy or potency?
There is quite a bit of data with aliskerin showing that it basically results in a similar degree of blood pressure lowering to any other anti-hypertensive class, and the drug has been compared head to head in hypertension studies with ACE inhibitors, with ARBs, with calcium channel antagonists and with diuretic therapy-- the four major classes that are in common use. So, it is as good at blood pressure lowering as the best drugs that we already have out there and, in some cases, better.

In addition, there is an enhancement of blood pressure lowering when you combine aliskerin with various classes, in particular when you add aliskerin to, say, a diuretic, as well as when you add it to an ARB. That’s very interesting because we know that when we use ACE inhibitors or ARBs, we don’t get complete blockade of the RAAS system.

That has led to the idea of combining multiple RAAS inhibitors. We have had success in using ACE inhibitors with ARBs, for example, in diabetic nephropathy. We’ve had somewhat less success, but some success, in combination therapy in heart failure; but it’s been a little bit disappointing, and that may be because ACE inhibition and ARB usage together may not be the most natural way to use combination therapy. Using a direct renin inhibitor blocks the point of activation of the entire system and gives you more complete blockade.

Family physicians often struggle with combination therapy and hypertension. They are aware that combination therapy is required in almost all patients with hypertension and in all patients with diabetic nephropathy. Combination therapy with an ACE and an ARB has often been used as a strategy to maximally inhibit the RAAS System; however, it is very important for family physicians to note that the combination of an ACE inhibitor with an ARB results in a very modest reduction in blood pressure; in fact, it comes at a significant cost of side effects.

So, if we were to treat hypertension, a strategy of using an ARB or an ACE inhibitor combined with another agent that work at different points within the RAAS cascade, and offered similar or less of a side effect profile than combining an ACE and ARB, would greater aid blood pressure reduction.

As you know, the definition of hypertension--140/90, now 130/80-- and the treatment targets continue to float. What is the official treatment target for the high risk patient these days?
In general, our CHEP guidelines, Canadian Hypertension Education Program, still advocate a target blood pressure of below 140/90 in the majority of patients with hypertension. The most important sub-group in which a lower blood pressure target is recommended are those with diabetes, and especially those with diabetic nephropathy, where we have the target of 130/80.

There’s a lot of discussion about Brain Natriuretic Peptide (BNP) these days. Can you elaborate?
BNP stands for Brain Natriuretic Peptide, which is released by the cardiac ventricles in response to increased wall pressure, or basically stretch, of the ventricular myocardium.

Conditions that result in stretch or stress on the myocardium results in the release of BNP, and the most common example is heart failure. BNP first made its name largely because it was found to be a very good predictor of the likelihood of having heart failure, and a good predictor of the severity and outcome of heart failure.

BNP was first tested in the emergency room, where for patients presenting with shortness of breath ,the diagnosis of heart failure can be a fairly difficult one to make clinically. Not everyone with heart failure has an abnormal chest x-ray. So, an elevated level of BNP increases the diagnostic acumen of physicians in diagnosing heart failure.

Beyond that, we’ve learned that even in patients without heart failure, but who have a certain atherosclerotic burden—such as, people with established vascular disease--an increased BNP level predicts long term outcome. So, BNP has really come to be regarded as a fairly valuable tool to help predict risk in people who already have heart failure.

Is BNP a widely-used tool tertiary care centers currently?
It is not yet widely used for clinical purposes, but is slowly being adopted into certain ER and risk-stratification protocols.

We do not yet have the link that providing an intervention that is associated with the reduction in BNP changes outcome. That link, I think, is necessary for BNP to become a more widely-used clinical tool in community practice. Having said that, major guidelines are moving more and more towards the adoption of a variety of different markers of risk to help better risk stratify patients in determining which patients are most eligible for which therapy.

How would you say it compares to hsCRP, high sensitivity C-reactive protein?
Bio-markers have been a great interest in prognostication, and CRP certainly has been one of the bio-markers that has been proposed today as an important marker in addition to LDL, apo-A, apo-A1, and many other bio-markers of risk.

I believe recent publications demonstrated that BNP was an independent prognosticator of poor outcomes and, that in a multivariate analysis, was independent of other inflammatory markers and other known conventional risk markers.

There’s a lot of discussion about pleiotrophic effects--added benefits beyond the stated one. Will this new class of agents, for example, be used in primary prevention in even non-hypertensive patients because of these added effects?
The beyond-class effects, pleiotrophic effects, is an area of great interest, particularly with both RAAS inhibitors and statins.

More recently, we have some great news from a trial called JIKEI that demonstrated that the strategy of using a RAAS blocker indicates that certain agents given to normotensive people, who had a blood pressure of 139 to begin with, compared with conventional management but did not include an ARB, was associated with a reduction in the composite of cardiovascular mortality and morbidity--close to a 40 per cent reduction in stroke. That speaks volumes to the so called pleiotrophic or beyond blood pressure effect that are seen with the RAAS inhibitors.

Aliskerin is an effective anti-hypertensive agent, providing a valuable tool in our arsenal of drugs, both in monotherapy and combination therapy, to help battle this problem of hypertension.

Recent data show us that, in fact, in North America and the western world, the lifetime risk of developing hypertension for an infant born today is over 90 per cent. So, in fact, all of us are going to end up with hypertension if we live long enough. And we end up needing at least two or three different classes of drugs often to better manage hypertension.

The real question is that though ACE inhibitors offer vascular or cardio protection beyond blood pressure lowering, do ARBs offer that as well, will aliskerin and Direct Renin Inhibitors offer that. That question is being addressed by a variety of clinical trials very specifically--to determine if there are additional benefits beyond blood pressure lowering.

There are studies with aliskerin compared to placebo to look at the incidence, for example, of left ventricular hypertrophy, which we know is strongly associated with poor outcome in hypertension.
The ALOFT study evaluates patients with systolic heart failure who have elevated BNP as a poor prognostic marker, who are already optimally treated with an ACE inhibitor or ARB, and randomizing them to aliskerin or placebo, to see if there is a beneficial effect on lowering the BNP levels. There is also a trial in diabetic nephropathy.

What is your final parting message on hypertension and cardiovascular disease?
For family physicians, I would like to leave the following message: and that you are the gatekeepers of cardiovascular risk reduction and you have the opportunity to arrest the continuum of cardiovascular disease early.

By the time people like Dr. Gupta and myself see patients, they have progressed far into the continuum of cardiovascular risk where aggressive secondary prevention strategies are required. The care gap in the management of hypertension continue to escalate and, in fact, it gets even worse as major organizations throughout the world lower the threshold of what is acceptable blood pressure target.

Combination therapy is an essential component of optimal management, and using an RAAS blocker over other conventional therapies may offer not simply a reduction in blood pressure, but also the opportunity to afford some of these so called “pleiotrophic” effects beyond the blood pressure benefit. Furthermore, combination strategies with some of the newer molecules, such as Direct Renin Inhibitors, should help close that treatment gap effectively.


Dr. Shafiq Qaadri is a Toronto family physician and Continuing Medical Education lecturer. www.doctorQ.ca

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