Matters of the heart

Drugs are supposed to provide relief from disease symptoms, but most drugs come with adverse effects. Therefore doctors have to balance relief with risks, especially when dealing with the cardiovascular system. Arshiya Khan reviews the most common drug-induced heart failures

The incidence of heart failures was two percent to five percent about 20 years back. Today, this has increased to five to 20 percent. There are many reasons for this increase, including improved diagnostic methods, the tendency to use high doses of anthracycline groups of drugs, (drugs which are used in leukaemia therapy to prevent cell division by disrupting the structure of the DNA), limited cardio protection, prolonged survival time of patients with malignancies and combined drug treatments with multiple cardio toxic drugs leading to synergistic cardio toxicity.

The incidence of drug induced heart failures in India varies depending on the kind of drug used. For example, anti-cancer drug called anthracycline has cardiac toxicity to the tune of 0.4-41 percent. "The death rate of anthracycline drug induced heart failure varies from 25 percent to 50 percent, which is much more than non-drug induced heart failure (HF)," informs Dr Bhaskar Shah, Interventional Cardiologist, Asian Heart Institute. And this is the same globally. "There is no significant racial difference in incidence of heart failures. However, due to the overall increase in the life span of a patient with heart disease and cancer due to better diagnostic and treatment modalities, we see more such patients now," says Dr Zakia Khan, Interventional Cardiologist, Wockhardt Hospital.

Deep inside the ventricles

Cardiac failure is a syndrome, which occurs when the heart fails to pump sufficient amount of blood to meet the metabolic demands of the body. The symptoms of acute cardiac failure include dyspnoea (shortness of breath), tachycardia (unusually fast beating of the heart), hypotension and confusion. These arise due to a combination of salt and water retention, increased venous pressure and inadequate organ perfusion. Chronic cardiac failure is characterised by dyspnoea, fatigue, ankle oedema, dizziness, palpitations, wheeze, chest discomfort and cough.

Drugs too can induce or provoke cardiac failure. This can occur through an increase in preload (volume overload), an increase in afterload (resistance), or cardiac dysfunction.

Drugs implicated include carbenoxolone, mineralocorticoid steroids such as fludrocortisone, and non-steroidal anti-inflammatory drugs (NSAIDs). Clinically detectable oedema (swelling) can be seen in three to five per cent of patients treated with NSAIDs and this could aggravate heart failure. Prolonged treatment with high doses of ritodrine (ritodrine hydrochloride, a tocolytic drug, used to stop premature labour), has been reported to cause cardiac failure.

Drugs with negative inotropic (an inotropic heart drug is one that affects the force with which the heart muscle contracts), cardiotoxic or arrhythmogenic effects may cause cardiac dysfunction. The role of b-blockers in cardiac failure has changed dramatically in recent years. Historically, the drugs have been contraindicated due to their negative inotropic action, which weakens cardiac contractility movements in left ventricular function, suggesting that they may have a role in carefully selected patients.

Adverse reactions affecting the cardiovascular system are common. There are some predictable type A reactions, for example the undesirable cardiac effects of cardioactive drugs such as digoxin and antiarrhythmics (antiarrhythmic agents are a group of drugs that are used to suppress fast rhythms of the heart), but many of these reactions are less predictable and they are not unique to cardiovascular drugs. For example, the cytotoxic agent doxorubicin can cause heart failure and appetite suppressants can cause heart valve disorders.

The newer calcium antagonists have reduced cardio depressant actions and may be used cautiously in patients with cardiac failure. Therapy should be withdrawn if symptoms appear. If cardiac failure is believed to be drug-induced the agent responsible should be stopped. Disease management involves lifestyle modification and treatment with diuretics and ACE inhibitors. Over-the-counter (OTC) medicines which should be discouraged in patients with heart failure include some antacids, effervescent preparations with high sodium content, and NSAIDs.

Why a heart failure?

Dr Zakia Khan, Interventional Cardiologist, Wockhardt Hospital

There are patients who are at a higher risk of heart failures by consuming these drugs. These would include patients with pre-existing heart disease, patients with high dose of treatment, and patients on multi-drug regimen. Patients with low body surface area are also more likely to suffer from cardio toxicity. Also at risk are patients with co-existing coronary artery disease, pre-existing cardiac dysfunction, patients who have received radiation therapy (1.6 times higher risk), simultaneous administration of multiple cardio toxic drugs, improper nutrition and patients with diabetes. "So for patients with drug induced HF, the drug causing HF should be withdrawn and standard therapy of HF should be given, however the response to the therapy is not as good," adds Shah.

The alternate way

Where there is a will, there is a way. These drugs which induce heart failures can to some extent be treated by alternate medicines. "Use of free radical scavengers, combined with anti cancer drugs eg. probucol, dexrazoxane, to reduce their cardiotoxicity, can be used as an alternate way of treatment," says Khan. Prevention of adriamycin (an active medicine against many cancers, it is one of the older chemotherapy drugs, in use for decades), induced HF by use of free radical scavengers and anti oxidants may reduce cardiotoxicity in some patients.

At present, the most effective protection of cardiomyocytes during therapy with adriamycin is with dexrazoxane. This preparation chelates or traps intracellular iron. This results in a decrease of the level of free radicals generated by iron catalysed pathways. This appears to be the most important pathway in the pathogenesis of drug induced HF. Dexrazoxane causes two to three fold decrease in the risk of adriamycin induced HF. Another antioxidant - probucol is raising hopes for selective cardio protection during adriamycin induce HF, informs Shah.

Available data suggest that circulating markers such as cardiac troponins (regulatory proteins of the thin actin filaments of cardiac muscle) and brain natriuretic peptide could potentially be useful for predicting cardiac toxicity with adriamycin. Elevated levels of cardiac troponins correlate with adriamycin induced cardiac damage. Raised levels indicate significantly greater decrease in left ventricular ejection fraction (LVEF).

The other alternate method is by using ion exchange technology. Ion channels are a relatively unexplored drug target class without many technologies available to functionally interrogate them unlike the G protein coupled receptors, which are a proven drug target class and heavily screened. Ion channels are experiencing a renewed interest from pharma and drug discovery companies. Deployment of ion channels is primarily driven by the large number of diseases and therapeutic areas, attributable to ion channel dysfunction. Some of these therapeutic areas include congenital, CNS, skeletal muscles, kidney disorders, pain and cancer. This may help in reducing the dose of the drug, its side effects and may achieve targeted delivery.

Knowing it all

Patients who are on anti-cancer drugs are well aware about cardiac side effects as they are asked to frequently get their echocardiograms (ECGs) done before each cycle of chemotherapy. But Khan has another view, "The awareness may not be so much in patients of pre-existing heart disease who are on beta

blockers (old generation), painkillers, antiarrhythmics and anaesthetics." Doctors treating cancer patients are well aware of the risks. However general practitioners, pharmacists may not have as much awareness. Shah also points out that people who have pre-existing significant cardiac dysfunction, taking OTC painkillers can precipitate heart failure due to their action on renal blood supply. Therefore pharmacists should be aware of the drugs most likely to have adverse effects on the cardiovascular system and the patient groups at greatest risk from these problems. Factors predisposing a patient to cardiovascular toxicity include heart disease, uncorrected electrolyte abnormalities, and poor renal function. The potential contribution of OTC medicines should also therefore be considered. "Awareness of drug induced HF, especially with drugs like adriamycin, is extremely high among the medical fraternity: pharmacists, clinicians and doctors leading to develop-ment of guidelines for prevention, early detection and prompt management of same," says Shah.

Government initiatives

Regulatory authorities first started getting concerned about drug-induced heart failures in the eighties due to repeated documentation. Today governmental agencies and the International Conference on Harmonisation (ICH) recommend assessing the potential of a drug to prolong the QT interval as measured in the electro-cardiogram (ECG). Attempts to solve the problem included:

• Removal of drugs from the market by the FDA (eg. terfenadine, cisapride)
• Cardiac Arrhythmia Suppression Trial (CAST, 1991)
• Points to consider Document by the Committee for Proprietary Medicinal Products (CPMP/986/96)
• Guidelines by the International Conference on Harmonisation (ICH S7A and S7B, 2000, 2002)

Also there are specific guidelines on dosing, combination therapy and monitoring for development of cardiac dysfunction following chemotherapy. "Otherwise there are no regulatory bodies to stop sale of OTC painkillers to a patient with pre-existing significant cardiac dys-function," informs Khan.

The protocols and guidelines prescribed by regulatory authorities are not strictly followed by medical fraternity in India, leading to an increase in drug induced HF in India. Similarly our regulatory bodies are not very prompt and stringent in calling back drugs from the market. Awareness of the problems of drug induced heart failures is scant, which again increases the risks. "Lastly the cost of investigations for early detection and prevention of drug induced HF is prohibitively costly to be adopted across the board in our country", says Shah.

There is no escaping the fact that most drugs have side effects. What is important is to devise alternate ways to deal with the problem. While regulatory authorities and the medical fraternity work on reducing these effects, patients have no choice but to balance these 'matters of the heart'.

arshiya.khan@expressindia.com