Re: Expert recommends combination therapy for hypertension management —Need for caution


Prof. Emmanuel Okoro

The PUNCH newspaper of 12 June 2022 reported a Professor of Preventive Cardiovascular Medicine from Imperial College, University of London, the United Kingdom advising doctors in Nigeria to initiate hypertension treatment with combination therapy including those with ARBs and ACEIs. This was at a forum in Lagos organised by an international pharmaceutical company with a vested interest in hypertension therapy. The report, if true, raises some issues.

First, as a leading expert in clinical trials, the Professor in declaring new studies show combining existing BP treatments as initial therapy performs better than a single drug even to their maximum tolerable doses can be interpreted to also include lower doses combination of such medicines in a fixed ratio into a single pill (FDC). As a high-profile global scholar linked to studies involved with the development of FDCs, the pronouncement is expected to carry a lot of weight in academic and professional circles on how best to initiate hypertension treatment from available options and train doctors/specialists to do so.

The problem with this position is that individual blood pressure (BP) medicine of different classes is not equally always effective everywhere and its effectiveness can depend on race and genetic makeup.  

This means that what works best in one group may not be appropriate in another. That is why in good health systems like in the UK, a market only 1/3rd of Nigeria’s in size, treatment is best informed by research on the population of intended use and marketing. 

Nigeria is a huge health market for blood pressure treatments and is the largest country for black people anywhere in the world. The country should therefore defer to knowledge as a guide for its choice of treatment from available options if the treatment is to be effective and reflect value-for-money.  

True, there is a place for adding a second or even a third drug when blood pressure control is inadequate with one drug alone. But for any FDC to be valid, the component 

drugs must contribute to the observed BP reduction at the doses combined in a meaningful way and reflect value for money relative to BP fall induced by each component drug used alone to their highest tolerable dose.

And despite WHO endorsement of FDCs, no published research in Nigeria’s population has affirmed that any of the numerous ARBs or ACEIs in Nigeria’s health market either used alone or as in FDCs deliver superior benefit to a Thiazide/Thiazides –like diuretics or a CCB (Calcium channel blocker ) – alone or together as separate pills sequentially added to their highest tolerable dose. 

Such head-to-head comparative studies can be expensive and take time to determine which options best suit the population of interest as initial BP therapy. 

Specifically, doing so with ARBs or ACEIs or other such newer BP medicines could appear wasteful and needless given their long history of widespread use in Europe and America and with a good record of safety and effectiveness before introduction into Nigeria’s health market.

Here lies the fallacy, because without this country-specific knowledge it can never be known with any degree of certainty whether the treatment choices now considered are the best of the available options and that they are appropriate and have good value-for-money given the expansive size of Nigeria’s market for hypertension therapy.

Even so, there is experience and a large body of data accumulated over 50 years that indicated that Thiazides and CCBs, two classes of BP medicines are particularly effective in Nigeria’s population with a robust record of safety. Both are relatively cheap and more affordable as generics compared to ARBs and other newer BP medicines increasingly prescribed alone or as FDCs frequently combined with a Thiazide or CCB in a fixed ratio. 

Contrary to expectation, FDCs especially the branded ones frequently cost more than the combined prices of their component drugs, and the price difference can sometimes be up to over 30 times higher relative to maximum doses of their component CCB or Thiazide, and for each unit fall in BP.  

Further, despite ARBs, ACEIs, and their FDCs flooding the market against Nigeria health laws and policies which restrict their use only to specialist care, deaths linked to uncontrolled BP continue to soar, increasing from 24.1 deaths/103 cases in 1990 to 47.1/103 in 2015 with one nation-wide survey also reporting just 14% of treated individuals in academic hospitals attaining BP targets that optimally prevent untimely death and life-changing outcomes like stroke. The reverse trend is most evident in Europe and North America where most treatments originate and can be the initial treatment choice.

Many experts have drawn attention to this paradox and issues of conflicts of interest and inappropriate designs of the many studies which informed the globalisation of FDCs, particularly those containing ARBs or ACEIs or other similar drugs as initial BP treatment. This also includes the lack of evidence of superiority in LMIC countries like Nigeria where FDCs are increasingly advocated and prescribed as first-line therapy.

The good thing though is that this is now a matter of growing concern as an ever-increasing number of people almost everywhere are being exposed to treatments less suitable to their health needs and treatment that escalate treatment costs and can also harm them when cheaper alternatives sometimes even better are available. 

Unfortunately, Nigeria has a recent but unenviable record of higher expenditure for interventions less tailored to its health needs relative to surrounding African countries often poorer that deliver better outcomes to their population at a lower cost. It requires restating that no appropriately designed local study is currently available that shows any ARB or other newer blood pressure drug types alone or as FDCs is superior in terms of health benefit relative to the maximum recommended dose of a CCB or thiazide to justify the astronomically high costs Nigerians sometimes pay for them. 

For example, 10mg daily of one CCB which cost N10 as generic results in comparable lower BP as one FDC containing 5mg or 10mg of the same CCB combined with one ARB but sold for N340 per pill as a branded FDC.

Such observations could fuel suspicion ARBs and other newer medicines types generally less effective in black Africans developed overseas may be marketing gimmicks designed to keep revenue flowing from innovator brands after patent expiration in the lucrative market of the first choice intended to benefit more. Especially without first showing FDC so created as combined with a CCB or a Thiazide, known to work well alone in Nigerians, delivers superior benefits that represent value for money before their widespread marketing as branded products.  

Coincidentally, Nigeria has an Essential Medicine List (EML) established by law which is regularly updated as new evidence emerges to ensure citizens receive only interventions that meet their health needs. This underlies why only CCBs and Thiazides are approved for widespread availability and use while ARBs, ACEIs, etc. alone or as FDCs are restricted for specialist care where experts can use them more appropriately in the few Nigerians not adequately controlled on a Thiazide or CCB or both at lower levels of treatment.  

To be sure, the majority in Nigeria ultimately would require more than one BP medicine type to achieve and sustain BP control, the real issue is not in the available drugs but how they are used which is often less than optimal.  

Treatment in Nigeria ought to be initiated with a CCBs or a Thiazide at the lowest effective dose and then titrated until the maximum tolerable dose is reached or BP is controlled. For those still uncontrolled, the thiazide or CCB can then be added sequentially to the maximum dose of the first drug until the highest tolerable dose is reached or BP controlled, whichever comes first-so called stepped care. This is not possible with any FDC including those with ARB combined with a thiazide or CCB and increasingly available at exorbitant prices, especially the branded ones. 

Treatment affordability often underlies why many do not achieve sustained BP control that saves lives and prevent complications like stroke. And not all costs are justifiable and some result from choosing higher-cost interventions when cheaper alternatives sometimes better are available.

Fortunately, Nigeria’s university system at the commanding heights of health care delivery has a rich heritage of guiding people in Nigeria with hypertension on how to meet their 

health needs based on local research. However, it seems unlikely that the Professor believed the capacity to do so still existed, otherwise there would have been less enthusiasm in lecturing his Nigerian counterparts that initiating hypertension treatment with a two-drug combination that includes ARB or ACEI was best for their compatriots based on research in Europe and America. 

This is something clearly at variance with Nigeria’s sovereign national health laws and policies designed to protect citizens from exploitation and harm. The impression need not be created, even if inadvertently, that sacrificing Nigerian lives for profits is okay.

Finally, experts who train doctors and specialists ought to guide against being unintentionally associated with unholy alliances that advance such motives camouflaged as academic endeavors.

References are available on request.

Emmanuel Okoro MB; B.Ch (Nigeria), Professor in Medicine, wrote from the University of Ilorin. Email: [email protected]   

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