PURPOSE: This article seeks to objectively review the clinical trial evidence to determine whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) have special cardiovascular protective effects.
METHODS: An objective review of the clinical trial evidence.
RESULTS: Clinical trials in hypertensive patients comparing ACEI and ARB with other drugs generally showed no difference in the primary cardiovascular outcome (United Kingdom Prospective Diabetes Study Group, Captopril Prevention Project, Swedish Trial in Old Patients with Hypertension 2, Japan Multicenter Investigation for Cardiovascular Diseases-B Randomized Trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, Second Australian National Blood Pressure Study Group, Valsartan Antihypertensive Long-Term Use Evaluation). Where the primary, or major secondary, cardiovascular end-point favors one of the treatment arms, it was always the arm with the lower achieved blood pressure that saw the better clinical result as in Losartan Intervention For Endpoint Reduction in Hypertension Study, Captopril Prevention Project, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and Valsartan Antihypertensive Long-Term Use Evaluation. Trials comparing ACEI or ARB against placebo in patients at high risk of cardiovascular events have not showed a consistent result; cardiovascular outcomes were reduced in Heart Outcomes Prevention Evaluation, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease, and the Jikei Heart Study, but were not significantly reduced in Perindopril Protection Against Recurrent Stroke Study, Comparison of Arnlodipine vs Enalapril to Limit Occurrences of Thrombosis Trial, Prevention of Events with ACEIs Trial, Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease Trial, and Prevention Regimen for Effectively Avoiding Second Strokes Trial. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, combining ACEIs with ARBs in high-risk patients did not reduce cardiovascular or renal outcomes compared with ACEI monotherapy alone. This absence of a reduction in cardiovascular outcome from the ACEI and ARB combination arm is further evidence suggesting that these drugs do not have any special cardiovascular protective effect. This objective review thus shows that the rennin-angiotensin antagonists do not have special cardiovascular protective properties.
CONCLUSION: The key to reducing cardiovascular outcome is to appropriately control blood pressure as well as to treat all other coronary risk factors.
Mahathir Mohamad was born in 1925 in Alor Star, Kedah. He entered the King Edward VII College of Medicine in Singapore in 1947 and graduated in 1953. His years in the medical school equipped young Mahathir with the training necessary to assess and diagnose a problem, before dispensing the appropriate treatment. Throughout his later years in the political limelight, Dr Mahathir recognised the very important role the medical college had in laying the strong foundation for his successful career. He joined UMNO in 1945, already interested in politics at the tender age of 20; he was first elected into Parliament in 1964. The vigorous expression of his candid views did not go down well during the troubled days following the 13 May 1969 racial riots and he was expelled from UMNO, his writings were banned, and he was considered a racial extremist. Nevertheless, his intellectual and political influence could not be ignored for long; he returned to Parliament in 1974, and became the fourth, and longest serving, Prime Minister of Malaysia in 1981. Dr Mahathir has found fame as a Malay statesman, and an important Asian leader of the twentieth century with much written, locally and internationally, debating his policies. This article, using Dr Mahathir's own writings, starts with his description of his early life, proceeds to look at his medical career, then touches on his diagnosis of the problems plaguing the Malays, before concluding with his views on the need to stand up to the prejudices and pressures of the Western world. Throughout his life, Dr Mahathir behaved as the ever-diligent medical doctor, constantly studying the symptoms to diagnose the cause of the ills in his community and country, before proceeding to prescribe the correct treatment to restore good health. It is a measure of his integrity and intellectual capability that he did not seek to hide his failures, or cite unfinished work in an attempt to cling to political power.
The landmark HMG-CoA reductase inhibitor (statin) studies have practical lessons for clinicans. The 4S trial established the importance of treating the hypercholesterolaemic patient with cardiovascular heart disease. Next, WOSCOPS showed the benefit of treating healthy, high-risk hypercholesterolaemic men. CARE, a secondary prevention trial, showed the benefit of treating patients with cholesterol levels within normal limits. This was confirmed by the LIPID trial, another secondary prevention study, which enrolled patients with cholesterol levels 155-271 mg/dl (4-7 mmol/l). The importance of treating patients with established ischaemic heart disease, and those at high risk of developing heart disease, regardless of cholesterol level, was being realized. In the MIRACL trial, hypocholesterolaemic therapy was useful in the setting of an acute coronary syndrome, while the AVERT study showed that aggressive statin therapy is as good as angioplasty in reducing ischaemic events in patients with stable angina. By showing the value of fluvastatin after percutaneous intervention, LIPS confirmed that benefit is a class action of the statins. The HPS randomized over 20 000 patients, and showed beyond doubt the value of statins in reducing cardiovascular events in the high-risk patient. Although PROSPER showed benefit in treating the elderly patients above 70 years, statin therapy in this trial was associated with an increase in cancer incidence. The comparative statin trials, PROVE-IT, REVERSAL, Phase Z of the A to Z, ALLIANCE and TNT, all showed that high-dose statins will better reduce cardiovascular events in the high-risk patient, although the adverse effects of therapy will also be increased. ALLHAT-LLT, ASCOT-LLA and CARDS showed that for statin therapy to demonstrate a significant benefit, hypertensive or diabetic patients must be at sufficiently high risk of cardiovascular events. The emphasis is now on the risk level for developing cardiovascular events, and treatment should target the high-risk group and not the lipid level of the patient. No therapy is free of adverse effect. Treatment of those most at risk will bring the most benefit; treatment of those not at high risk of cardiovascular disease may expose patients who would not benefit much from therapy to its adverse effects.
Cholesterol reduction reduces ischaemic cardiovascular morbidity and mortality in the asymptomatic healthy population as well as in those with known coronary artery disease. Angiographic studies have also demonstrated regression of atherosclerotic plaques as well as retardation of new atheroma formation with such therapy. Yet, there is a consistent inability to reduce overall mortality in cholesterol-lowering drug trials. An excess of suicide, homicide and violence has been attributed to cholesterol reduction interfering with membrane lipids and receptors, leading to aggressive behaviour. The risk and benefits of cholesterol reduction must thus be weighed in the individual patient; it is more useful in those with known coronary artery disease who are at high risk of subsequent ischaemic cardiovascular events.
A 61-year old lady presented clinically in unstable angina with ST-segment depression typical of myocardial ischemia. However, coronary arteries were completely normal at angiography. Exercise testing reproduced symptoms and ST-segment depression. A diagnosis of Syndrome X was made, an uncommon disorder of myocardial ischemia with normal coronary anatomy and excellent prognosis.
Evidence thus far still supports the contention that fish derived omega-3 fatty acids, EPA and DHA, are good for heart patients. But this controversy tells us something about the medical research, and the acquisition and application of medical knowledge. Being scientists, doctors try to perform studies as rigorously as possible with randomised, placebo-controlled trials and using tests of statistical significance. But since the studies are on humans, with all their individual differing habits and inconsistencies, different results are produced by different researchers. And so while medicine is a science, in that the trials are scientifically conducted, the interpretation of the results, and in particular its application for the individual patient, is very much an art. A good doctor, like the good artist, must spend much time, energy and effort sieving through the good from the not so good data before coming out with the correct picture. Only by keeping an unbiased, inquisitive mind can the evidence be reviewed to solve the problem at hand. Almost always, the balance of data will favour a particular stand. In this day when newspapers are full of medical articles, a family physician has to be educated, interested and inquisitive to be a source of accurate and relevant information for the patients.
The comparative anti-hypertensive drug trials conducted to assess their cardiovascular protective efficacy actually produce compatible, not conflicting, results. In the last decade, there were 13 major comparative hypertension drug trials with the cardiovascular primary outcome being statistically equivalent in 11 of these 13 trials, involving over 90 percent of the randomised 168,593 patients. Where secondary outcomes favour a drug in these trials, that arm has a significantly lower treated blood pressure as in LIFE, VALUE, ASCOT and ALLHAT. Controversy occurs in seeking to attribute the benefit to drug effect; if the benefit is attributed to the lower achieved blood pressure, then the trials become consistent. The safety and value of diuretics, beta-blockers, calcium-blockers, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in reducing blood pressure, and in reducing clinical cardiovascular outcomes, is now clearly established. Overall, the importance of tight blood pressure control in reducing cardiovascular outcomes must be emphasised. Physicians should concentrate on achieving good blood pressure control, which often requires a combination of several antihypertensive drugs.
Since hypertension is generally asymptomatic, in treating hypertension we are actually seeking to prevent target organ damage and reduce adverse clinical outcome. There have been numerous large clinical trials addressing the question of whether any antihypertensive drug has special protective effects on the cardiovascular and renal systems in addition to the benefit from blood pressure (BP) reduction1-15. In seeking to correctly interpret the message from these trials, it is important to avoid the confusion that can occur when pharmaceutical companies seek to make the results suit their marketing needs 16-18. The aim of this article is thus to provide an unbiased review of the value of the different antihypertensive drugs for the clinician treating essential hypertension in Malaysia.
Increasing observational and experimental trial data have shown that mental stress can lead to an increase in adverse clinical cardiovascular events. Mental stress affects the heart by inducing ischaemia and precipitating myocardial infarction (MI) or direct myocardial injury. Mental stress leads to systemic inflammation. Inflammation is known to cause rapid atheromatous plaque progression, instability and thrombosis-the classic type 1 MI. Inflammation can also lead to type 2 MI or myocarditis and injury. The published data linking systemic inflammation, mental stress and cardiovascular disease will be reviewed to establish the linkage between mind and heart, thereby highlighting the importance of holistically managing the patient, not only addressing separate organ systems. Finally, recent trial evidence showing the value of anti-inflammatory drugs in cardiovascular and mental conditions will be briefly considered.
The hypertensive patient with type 2 diabetes is especially at risk of adverse cardiovascular events. The United Kingdom Prospective Diabetes Study (UKPDS) and Hypertension Optimal Treatment (HOT) studies suggested that treatment to a lower target blood pressure resulted in better prevention of clinical disease in these patients. Most trials comparing antihypertensive drugs have shown only minimal differences between the various agents. The evidence from the trials suggests that diuretics, beta-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and the angiotensin-receptor antagonists (ARBs) will all successfully reduce adverse clinical events. The largest of the comparative hypertensive drug trials, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), demonstrated that a diuretic has a better hypotensive effect, and was more successful in preventing many aspects of cardiovascular disease compared with CCBs and ACE inhibitors. The importance of good blood pressure control and the general equivalence of antihypertensive drugs were again shown in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, which compared an ARB with a CCB. Choice of antihypertensive agent should be individualized and guided by the presence of concomitant clinical disease and the need to protect any specific target organ system in the diabetic hypertensive. Diuretics, being potent hypotensive drugs with clearly demonstrated clinical benefit, should form part of the antihypertensive regimen of most diabetic hypertensives. ACE inhibitors and ARBs are especially useful in preventing nephropathy. Most patients will require a combination of antihypertensive drugs to achieve tight blood pressure control of under 130/80 mm Hg in the diabetic hypertensive. The clinician should concentrate on seeking this lower target blood pressure rather than be excessively concerned about which is the best antihypertensive agent.
The incidence of West syndrome (WS) was determined by a search of reports of electroencephalograms (EEG) recorded in 1998 and 1999 in all public hospitals in Singapore. Amongst records of patients born in 1998, nine were found with EEG features of hypsarrhythmia or modified hypsarrhythmia with onset of seizures between January 1,1998 and December 31, 1999. The medical records of these patients were reviewed. The population of children born in 1998 was 43,664. In 1998 and 1999, 67% of all hospital admissions for patients 2 years or younger in Singapore were in public hospitals. The cumulative incidence of WS in Singapore corrected for the percentage of hospital admissions to public hospitals was 3.1/10,000 live births. The corrected cumulative incidences in Chinese, Malays and Indians were 2.7, 3.1 and 3.3 per 10,000, respectively. Three cases were idiopathic; three were due to congenital structural lesions of the brain; one each had periventricular leucomalacia, intracranial hemorrhage and severe intrauterine growth retardation. None of the patients were normal at follow up. The three patients with idiopathic WS had mild global developmental delay and the other six cases had cerebral palsy and severe mental retardation. With the best modern medical treatment, possibly only two of the nine cases of WS may have been prevented.
The aim of this review is to objectively access the trial evidence on the role of omega-3, red yeast rice and garlic in preventing clinical cardiovascular events. Given the large number of clinical trials favoring statin use in cardiovascular disease, it is important to see if evidence is available for these supplements and whether they could replace statin therapy.